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Rare syndromic craniosynostosis or isolated multisuture synostosis v4.178 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from 304110; Craniofrontonasal syndrome 304110 to Craniofrontonasal dysplasia, OMIM:304110
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 TMEM251 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: TMEM251.
Tag gene-checked tag was added to gene: TMEM251.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 TMEM251 Achchuthan Shanmugasundram commented on gene: TMEM251: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.

The OMIM entry for this gene is OMIM:619332, which has been cross-checked with Ensembl, HGNC and G2P. Hence, gene-checked tag has been added.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 SOX6 Eleanor Williams Tag Q2_23_promote_green was removed from gene: SOX6.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 RSPRY1 Eleanor Williams Tag Q2_23_promote_green was removed from gene: RSPRY1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 PRRX1 Eleanor Williams Tag Q2_23_promote_green was removed from gene: PRRX1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 NFIX Eleanor Williams Tag Q2_23_promote_green was removed from gene: NFIX.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 MAN2B1 Eleanor Williams Tag Q2_23_promote_green was removed from gene: MAN2B1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 KAT6B Eleanor Williams Tag Q2_23_promote_green was removed from gene: KAT6B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 IL6ST Eleanor Williams Tag Q2_23_promote_green was removed from gene: IL6ST.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 IFT140 Eleanor Williams Tag Q2_23_promote_green was removed from gene: IFT140.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 FGF9 Eleanor Williams Tag Q2_23_promote_green was removed from gene: FGF9.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 FBXO11 Eleanor Williams Tag Q2_23_promote_green was removed from gene: FBXO11.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 FBN1 Eleanor Williams Tag Q2_23_promote_green was removed from gene: FBN1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 CDK13 Eleanor Williams Tag Q2_23_promote_green was removed from gene: CDK13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 BCL11B Eleanor Williams Tag Q2_23_promote_green was removed from gene: BCL11B.
Tag Q2_23_NHS_review was removed from gene: BCL11B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 ARID1B Eleanor Williams Tag Q2_23_promote_green was removed from gene: ARID1B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 AHDC1 Eleanor Williams Tag Q2_23_promote_green was removed from gene: AHDC1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 ADAMTSL4 Eleanor Williams Tag Q2_23_promote_green was removed from gene: ADAMTSL4.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 SOX6 Eleanor Williams edited their review of gene: SOX6: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 RSPRY1 Eleanor Williams edited their review of gene: RSPRY1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 PRRX1 Eleanor Williams edited their review of gene: PRRX1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 NFIX Eleanor Williams edited their review of gene: NFIX: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 MAN2B1 Eleanor Williams reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 KAT6B Eleanor Williams edited their review of gene: KAT6B: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 IL6ST Eleanor Williams reviewed gene: IL6ST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 IFT140 Eleanor Williams edited their review of gene: IFT140: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 FGF9 Eleanor Williams edited their review of gene: FGF9: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 FBXO11 Eleanor Williams reviewed gene: FBXO11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 FBN1 Eleanor Williams edited their review of gene: FBN1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 CDK13 Eleanor Williams reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 BCL11B Eleanor Williams reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 ARID1B Eleanor Williams reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 AHDC1 Eleanor Williams edited their review of gene: AHDC1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.174 ADAMTSL4 Eleanor Williams edited their review of gene: ADAMTSL4: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 SOX6 Eleanor Williams Source Expert Review Green was added to SOX6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 RSPRY1 Eleanor Williams Source Expert Review Green was added to RSPRY1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 PRRX1 Eleanor Williams Source Expert Review Green was added to PRRX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 NFIX Eleanor Williams Source Expert Review Green was added to NFIX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 MAN2B1 Eleanor Williams Source Expert Review Green was added to MAN2B1.
Source NHS GMS was added to MAN2B1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 KAT6B Eleanor Williams Source Expert Review Green was added to KAT6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 IL6ST Eleanor Williams Source Expert Review Green was added to IL6ST.
Source NHS GMS was added to IL6ST.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 IFT140 Eleanor Williams Source Expert Review Green was added to IFT140.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 FGF9 Eleanor Williams Source Expert Review Green was added to FGF9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 FBXO11 Eleanor Williams Source Expert Review Green was added to FBXO11.
Source NHS GMS was added to FBXO11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 FBN1 Eleanor Williams Source Expert Review Green was added to FBN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 CDK13 Eleanor Williams Source Expert Review Green was added to CDK13.
Source NHS GMS was added to CDK13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 BCL11B Eleanor Williams Source Expert Review Green was added to BCL11B.
Source NHS GMS was added to BCL11B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 ARID1B Eleanor Williams Source Expert Review Green was added to ARID1B.
Source NHS GMS was added to ARID1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 AHDC1 Eleanor Williams Source Expert Review Green was added to AHDC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.173 ADAMTSL4 Eleanor Williams Source Expert Review Green was added to ADAMTSL4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.172 SLC25A24 Sarah Leigh Publications for gene: SLC25A24 were set to 29100094; 29100093
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.171 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from Fontaine progeroid syndrome 612289; Gorlin-Chaudhry-Moss to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 MASP1 Achchuthan Shanmugasundram reviewed gene: MASP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33765348, 36980886; Phenotypes: 3MC syndrome 1, OMIM:257920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 KANSL1 Achchuthan Shanmugasundram reviewed gene: KANSL1: Rating: RED; Mode of pathogenicity: None; Publications: 26424144, 29093661, 36980886; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: None
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 SCARF2 Achchuthan Shanmugasundram reviewed gene: SCARF2: Rating: RED; Mode of pathogenicity: None; Publications: 29168297, 29620724, 36980886; Phenotypes: Van den Ende-Gupta syndrome, OMIM:600920, craniosynostosis, MONDO:0015469; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 ZCCHC11 Achchuthan Shanmugasundram gene: ZCCHC11 was added
gene: ZCCHC11 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ZCCHC11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZCCHC11 were set to 28808027; 36980886
Phenotypes for gene: ZCCHC11 were set to craniosynostosis, MONDO:0015469
Review for gene: ZCCHC11 was set to RED
Added comment: An individual was described with metopic synostosis and a novel de novo frameshift variant in ZCCHC11 (p.Glu1275fs) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.169 ZBTB20 Achchuthan Shanmugasundram gene: ZBTB20 was added
gene: ZBTB20 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 34429528; 36980886
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; craniosynostosis, MONDO:0015469
Review for gene: ZBTB20 was set to RED
Added comment: A de novo missense variant (c.1948A>C; p.Asn650His) was identified in an individual from the 100k genomes project with craniosynostosis, congenital heart disease, intellectual disability, and spinal anomalies (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.168 TWIST2 Achchuthan Shanmugasundram Publications for gene: TWIST2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.167 TWIST2 Achchuthan Shanmugasundram Mode of inheritance for gene: TWIST2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.166 TWIST2 Achchuthan Shanmugasundram reviewed gene: TWIST2: Rating: RED; Mode of pathogenicity: None; Publications: 31292255, 36980886; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.166 TMEM251 Achchuthan Shanmugasundram gene: TMEM251 was added
gene: TMEM251 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156; 36980886
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex, Ain-Naz type, OMIM:619345; craniosynostosis, MONDO:0015469
Review for gene: TMEM251 was set to RED
Added comment: Whole-exome sequencing identified two homozygous variants c.133C>T/ p.Arg45Trp (absent from gnomAD) and c.215dupA/ p.Tyr72Ter (2 alleles in gnomAD, annotated as pathogenic in ClinVar), in two families. Immunofluorescence and confocal studies show that the p.Arg45Trp mutant TMEM251 protein was targeted less efficiently to the Golgi complex compared to wildtype protein (PMID:33252156).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.165 SRCAP Achchuthan Shanmugasundram gene: SRCAP was added
gene: SRCAP was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SRCAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRCAP were set to 33288889; 36980886
Review for gene: SRCAP was set to RED
Added comment: One individual was described with a stop-gain variant in SRCAP (c.7303C>T; p.Arg2435Ter) in the Norwegian cohort (PMID:33288889).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.164 SPRY4 Achchuthan Shanmugasundram gene: SPRY4 was added
gene: SPRY4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SPRY4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPRY4 were set to 28808027; 36980886
Phenotypes for gene: SPRY4 were set to craniosynostosis, MONDO:0015469
Review for gene: SPRY4 was set to RED
Added comment: An individual was described with a heterozygous de novo variant in SPRY4 (p.Glu160Ter) (PMID:28808027). This gene has a low pLI (0) suggesting tolerance to loss-of-function.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.163 SP7 Achchuthan Shanmugasundram gene: SP7 was added
gene: SP7 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SP7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP7 were set to 35121733; 36980886
Phenotypes for gene: SP7 were set to craniosynostosis, MONDO:0015469
Review for gene: SP7 was set to RED
Added comment: A de novo missense variant (c.926 C>G; p.Ser309Trp) in SP7 was identified in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice (PMID:35121733).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.162 SMURF1 Achchuthan Shanmugasundram changed review comment from: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027)
Sources: Literature; to: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.162 SMURF1 Achchuthan Shanmugasundram gene: SMURF1 was added
gene: SMURF1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMURF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMURF1 were set to 28808027; 36980886
Phenotypes for gene: SMURF1 were set to craniosynostosis, MONDO:0015469
Review for gene: SMURF1 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.161 SMC1A Achchuthan Shanmugasundram gene: SMC1A was added
gene: SMC1A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMC1A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: SMC1A were set to 29037998; 36980886
Phenotypes for gene: SMC1A were set to Cornelia de Lange syndrome 2, OMIM:300590; craniosynostosis, MONDO:0015469
Review for gene: SMC1A was set to RED
Added comment: An X-linked dominant variant (c.3581A>G; p.Tyr1194Cys) was identified in an individual with Cornelia de Lange syndrome (characterised by dysmorphic facial features, growth, and developmental delay and syndromic craniosynostosis). Their mother was mosaic for the variant (PMID:29037998).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.160 SMARCD2 Achchuthan Shanmugasundram gene: SMARCD2 was added
gene: SMARCD2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMARCD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCD2 were set to 28808027; 36980886
Phenotypes for gene: SMARCD2 were set to craniosynostosis, MONDO:0015469
Review for gene: SMARCD2 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in SMARCD2 (p.Arg73Ter) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.159 SMAD2 Achchuthan Shanmugasundram gene: SMAD2 was added
gene: SMAD2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD2 were set to 34429528; 36980886
Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, OMIM:619656
Review for gene: SMAD2 was set to RED
Added comment: A de novo variant in SMAD2 (c.1223T>C; p.Leu408Pro) was identified in an individual within the craniosynostosis cohort of the 100k genomes project. The variant was absent from gnomAD and was predicted to affect a residue within a functional domain (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.158 SIX2 Achchuthan Shanmugasundram gene: SIX2 was added
gene: SIX2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SIX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIX2 were set to 26581443; 36980886
Phenotypes for gene: SIX2 were set to six2-related frontonasal dysplasia, MONDO:0044628; craniosynostosis, MONDO:0015469
Review for gene: SIX2 was set to RED
Added comment: A family with a dominantly inherited craniofacial phenotype (frontal bossing with high hairline, ptosis, hypertelorism, broad nasal tip, large anterior fontanelle, cranial base anomalies, and sagittal synostosis (only confirmed in one individual)) were identified on chromosomal microarray to harbour a heterozygous 108.3 kilobase deletion of chromosome 2p21 (disrupting SIX2 and the surround non-coding DNA) (PMID:26581443).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.157 SH3BP4 Achchuthan Shanmugasundram gene: SH3BP4 was added
gene: SH3BP4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SH3BP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SH3BP4 were set to 35080095; 36980886
Phenotypes for gene: SH3BP4 were set to craniosynostosis, MONDO:0015469
Review for gene: SH3BP4 was set to RED
Added comment: A patient was described with a recessive variant in SH3BP4 (c.128C>A; p.Pro43His) in the Norwegian craniosynostosis cohort. The variant has a CADD score of 33 and a gnomAD allele frequency of 9.6 x 10-5 (no homozygotes are reported in gnomAD). The patient presented with a Chiari I malformation, exophthalmos, eating difficulties as an infant, microcephaly, recurrent infections, dysmorphic features, Kabuki-like syndrome, and pan-synostosis. This patient also harbours two variants in KMT2D: c.11599C>A; p.Gln3867Lys (CADD = 22) and c.7182C>A; p.Ser2394Arg (CADD = 20); gnomAD frequency 1.2 x 10-5 and absent, respectively (PMID:35080095).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.156 SCN8A Achchuthan Shanmugasundram changed review comment from: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528)
Sources: Literature; to: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.156 SCN8A Achchuthan Shanmugasundram gene: SCN8A was added
gene: SCN8A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SCN8A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN8A were set to 34429528; 36980886
Phenotypes for gene: SCN8A were set to craniosynostosis, MONDO:0015469
Review for gene: SCN8A was set to RED
Added comment: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.155 RASAL2 Achchuthan Shanmugasundram gene: RASAL2 was added
gene: RASAL2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: RASAL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RASAL2 were set to 28808027; 36980886
Phenotypes for gene: RASAL2 were set to craniosynostosis, MONDO:0015469
Review for gene: RASAL2 was set to RED
Added comment: An individual was described with sagittal synostosis and a de novo variant in RASAL2 (p.Arg571Pro) (PMID:28808027)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.154 PUF60 Achchuthan Shanmugasundram gene: PUF60 was added
gene: PUF60 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUF60 were set to 36367278; 36980886
Phenotypes for gene: PUF60 were set to craniosynostosis, MONDO:0015469
Review for gene: PUF60 was set to RED
Added comment: A patient presenting with Verheij syndrome, characterised by craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay, was identified with a heterozygous variant in the splicing factor PUF60 (c.436C>T; p.Arg146Cys). They displayed fusion of the coronal and sagittal suture (PMID:36367278).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.153 PTH2R Achchuthan Shanmugasundram gene: PTH2R was added
gene: PTH2R was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PTH2R was set to Other
Publications for gene: PTH2R were set to 26044810; 36980886
Phenotypes for gene: PTH2R were set to craniosynostosis, MONDO:0015469
Review for gene: PTH2R was set to RED
Added comment: A boy presenting with sagittal and metopic synostosis was found to harbour a complex paracentric inversion involving 2q14.3 and 2q3. An intronic break of the PTH2R gene was
detected by whole genome sequencing and fluorescence in situ hybridisation (PMID:26044810).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.152 PSMD12 Achchuthan Shanmugasundram gene: PSMD12 was added
gene: PSMD12 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PSMD12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PSMD12 were set to 34429528; 36980886
Phenotypes for gene: PSMD12 were set to craniosynostosis, MONDO:0015469
Review for gene: PSMD12 was set to RED
Added comment: A heterozygous variant was identified in the UK 100k genomes project (parents were not available for testing): c.1284G>A; p.Trp428* (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.151 PSMC5 Achchuthan Shanmugasundram gene: PSMC5 was added
gene: PSMC5 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 28808027; 36980886
Phenotypes for gene: PSMC5 were set to craniosynostosis, MONDO:0015469
Review for gene: PSMC5 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in PSMC5 (p.Arg317Trp) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.150 PSMC2 Achchuthan Shanmugasundram gene: PSMC2 was added
gene: PSMC2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PSMC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PSMC2 were set to 28808027; 36980886
Phenotypes for gene: PSMC2 were set to craniosynostosis, MONDO:0015469
Review for gene: PSMC2 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in PSMC2 (p.Arg297Gly) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.149 POLR2A Achchuthan Shanmugasundram gene: POLR2A was added
gene: POLR2A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR2A were set to 35080095; 36980886
Phenotypes for gene: POLR2A were set to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, OMIM:618603; craniosynostosis, MONDO:0015469
Review for gene: POLR2A was set to RED
Added comment: A de novo insertion was identified in the Norwegian sequencing study: c.4329_4330delinsAA; p.Ala1444Thr. The variant is absent from gnomAD (v.2.1.1) but is not predicted to affect a functional domain. The patient displayed metopic synostosis, impaired motor skills, hypospadias, hypermobile joints and hyperactive behaviour (PMID:35080095).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.148 PITX2 Achchuthan Shanmugasundram gene: PITX2 was added
gene: PITX2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PITX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PITX2 were set to 36980886
Review for gene: PITX2 was set to RED
Added comment: Tooze et al has reviewed in PMID:36980886 from unpublished data that two cases of de novo missense variants are known with craniosynostosis, but not reported.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.147 OSTM1 Achchuthan Shanmugasundram Phenotypes for gene: OSTM1 were changed from AR osteopetrosis 5 to Osteopetrosis, autosomal recessive 5, OMIM:259720; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.146 OSTM1 Achchuthan Shanmugasundram Publications for gene: OSTM1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.145 OSTM1 Achchuthan Shanmugasundram Mode of inheritance for gene: OSTM1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 OSTM1 Achchuthan Shanmugasundram edited their review of gene: OSTM1: Changed phenotypes to: Osteopetrosis, autosomal recessive 5, OMIM:259720, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 OSTM1 Achchuthan Shanmugasundram changed review comment from: An individual was reported with osteopetrosis, craniosynostosis, and Chiari malformation type 1 and two novel homozygous variants in OSTEM1. The first was a missense variant c.265T>A (p.Val122Asp), which was considered neutral. The second variant was a synonymous change (c.108C>T) but was predicted to create a new donor splice site and disrupt mRNA processing (PMID:23772242).; to: An individual was reported with osteopetrosis, craniosynostosis, and Chiari malformation type 1 and two novel homozygous variants in OSTEM1. The first was a missense variant c.265T>A (p.Val122Asp), which was considered neutral. The second variant was a synonymous change (c.108C>T) but was predicted to create a new donor splice site and disrupt mRNA processing (PMID:23772242).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 OSTM1 Achchuthan Shanmugasundram reviewed gene: OSTM1: Rating: RED; Mode of pathogenicity: None; Publications: 23772242, 36980886; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 NTRK2 Achchuthan Shanmugasundram gene: NTRK2 was added
gene: NTRK2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: NTRK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NTRK2 were set to 27884935; 36980886
Phenotypes for gene: NTRK2 were set to Obesity, hyperphagia, and developmental delay, OMIM:613886; craniosynostosis, MONDO:0015469
Review for gene: NTRK2 was set to RED
Added comment: A heterozygous stop-gain variant was identified in an individual with unicoronal synostosis, language delay, hyperphagic obesity, and aggression (c.1330G>T; p.Gly444*). It was suspected that the variant arose de novo but the father’s sample was not available for testing (PMID:27884935).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.143 NAA25 Achchuthan Shanmugasundram gene: NAA25 was added
gene: NAA25 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: NAA25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NAA25 were set to 30152016; 36980886
Phenotypes for gene: NAA25 were set to craniosynostosis, MONDO:0015469
Review for gene: NAA25 was set to RED
Added comment: One individual was described with sagittal synostosis to harbour a de novo frameshifting variant in NAA25 (p.Phe359fs*) (PMID:30152016).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.142 MMP21 Achchuthan Shanmugasundram gene: MMP21 was added
gene: MMP21 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: MMP21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP21 were set to 34429528; 36980886
Phenotypes for gene: MMP21 were set to craniosynostosis, MONDO:0015469
Review for gene: MMP21 was set to RED
Added comment: Compound heterozygous variants (c.671_684del/ p.Val224Glyfs*29 and c.775C>G/ p.His259Asp) were identified in an individual within the 100kGP with heterotaxy and craniosynostosis (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.141 MED13L Achchuthan Shanmugasundram gene: MED13L was added
gene: MED13L was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: MED13L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MED13L were set to 28371282; 36980886
Phenotypes for gene: MED13L were set to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789; craniosynostosis, MONDO:0015469
Review for gene: MED13L was set to RED
Added comment: Two siblings exhibited an intragenic deletion of exons 3-14 resulting in MED13L haploinsufficiency syndrome (intellectual disability, developmental delay, heart defects and dysmorphic features). The deletion was inherited from their mother who showed low frequency mosaicism. The older sibling also presented with craniosynostosis (PMID:28371282).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.140 MACF1 Achchuthan Shanmugasundram gene: MACF1 was added
gene: MACF1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MACF1 were set to 28808027; 36980886
Phenotypes for gene: MACF1 were set to craniosynostosis, MONDO:0015469
Review for gene: MACF1 was set to RED
Added comment: An individual was described with sagittal synostosis and a novel splicing variant in MACF1 (IVS89+1G>A) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.139 KPTN Achchuthan Shanmugasundram Classified gene: KPTN as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.139 KPTN Achchuthan Shanmugasundram Gene: kptn has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.138 KPTN Achchuthan Shanmugasundram gene: KPTN was added
gene: KPTN was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: KPTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KPTN were set to 24239382; 36980886
Phenotypes for gene: KPTN were set to Intellectual developmental disorder, autosomal recessive 41, OMIM:615637; craniosynostosis, MONDO:0015469
Review for gene: KPTN was set to AMBER
Added comment: Four families were described with variants in KPTN and suspected craniosynostosis. Sagittal synostosis was confirmed in one individual from a family with three affected individuals. All families harboured a variant encoding p.Ser259*; this was homozygous in four individuals and in trans with another heterozygous variant (p.Met241_Gln246dup) in five individuals (PMID:24239382).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.137 KMT5B Achchuthan Shanmugasundram gene: KMT5B was added
gene: KMT5B was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: KMT5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT5B were set to 34429528; 36980886
Phenotypes for gene: KMT5B were set to craniosynostosis, MONDO:0015469
Review for gene: KMT5B was set to RED
Added comment: A de novo loss of function variant was identified within the 100kGP craniosynostosis cohort: c.557T>A; p.Leu186* (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.136 IFRD1 Achchuthan Shanmugasundram gene: IFRD1 was added
gene: IFRD1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IFRD1 were set to 35997807; 36980886
Phenotypes for gene: IFRD1 were set to craniosynostosis, MONDO:0015469
Review for gene: IFRD1 was set to RED
Added comment: A de novo variant was identified in a cohort of patients with lambdoid synostosis (p.Gly6fs*) (PMID:35997807).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.135 HIST1H1E Achchuthan Shanmugasundram gene: HIST1H1E was added
gene: HIST1H1E was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
new-gene-name tags were added to gene: HIST1H1E.
Mode of inheritance for gene: HIST1H1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H1E were set to 36118902; 36980886
Phenotypes for gene: HIST1H1E were set to craniosynostosis, MONDO:0015469
Review for gene: HIST1H1E was set to RED
Added comment: A patient with syndromic unilambdoid synostosis was found to harbour a frameshifting variant in HIST1H1E (c.433_434insC; p.Thr146Hisfs*50). The variant is reported as pathogenic for Rahman syndrome in ClinVar and absent from gnomAD (PMID:36118902).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.134 HDAC4 Achchuthan Shanmugasundram gene: HDAC4 was added
gene: HDAC4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
cnv tags were added to gene: HDAC4.
Mode of inheritance for gene: HDAC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HDAC4 were set to 33288889; 36980886
Phenotypes for gene: HDAC4 were set to craniosynostosis, MONDO:0015469
Review for gene: HDAC4 was set to RED
Added comment: A patient was described with two copy number variants: g.233110452_ 243028452 and del g.210300_ 8664358dup. The second variant was maternally inherited (PMID:33288889)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.133 H3F3B Achchuthan Shanmugasundram gene: H3F3B was added
gene: H3F3B was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: H3F3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: H3F3B were set to 33268356; 36980886
Phenotypes for gene: H3F3B were set to craniosynostosis, MONDO:0015469
Review for gene: H3F3B was set to RED
Added comment: In a cohort of 33 patients with H3F3A variants and 13 patients with H3F3B variants, 5/13 (~40%) individuals with H3F3B variants were reported with “craniosynostosis or abnormal head shape”. Of these, it is not clear if these were radiologically confirmed and what proportion of this subset of patients had synostosis compared to dysmorphic features (PMID:33268356).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.132 H3F3A Achchuthan Shanmugasundram gene: H3F3A was added
gene: H3F3A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: H3F3A were set to 33268356; 36980886
Phenotypes for gene: H3F3A were set to craniosynostosis, MONDO:0015469
Review for gene: H3F3A was set to RED
Added comment: In a cohort of 33 patients with H3F3A variants and 13 patients with H3F3B variants, 9/33 (~30%) individuals with H3F3A variants were reported with “craniosynostosis or abnormal head shape”. Of these, it is not clear if these were radiologically confirmed and what proportion of this subset of patients had synostosis compared to dysmorphic features (PMID:33268356).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.131 GLIS3 Achchuthan Shanmugasundram gene: GLIS3 was added
gene: GLIS3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: GLIS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLIS3 were set to 26259131; 36980886
Phenotypes for gene: GLIS3 were set to craniosynostosis, MONDO:0015469
Review for gene: GLIS3 was set to RED
Added comment: One patient was described with a variant in GLIS3 and sagittal craniosynostosis requiring surgical intervention. The patient harboured a homozygous deletion of exons 9 – 11; consanguinity was not confirmed but suspected (PMID:26259131).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.130 GPC4 Achchuthan Shanmugasundram gene: GPC4 was added
gene: GPC4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: GPC4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPC4 were set to 31292255; 36980886
Phenotypes for gene: GPC4 were set to craniosynostosis, MONDO:0015469
Review for gene: GPC4 was set to RED
Added comment: A variant in GPC4 was identified in an individual with syndromic craniosynostosis. The variant encoding p.Val152fs arose de novo in the mother (PMID:31292255)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.129 GLI2 Achchuthan Shanmugasundram gene: GLI2 was added
gene: GLI2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: GLI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GLI2 were set to 31292255; 36980886
Phenotypes for gene: GLI2 were set to craniosynostosis, MONDO:0015469
Review for gene: GLI2 was set to RED
Added comment: A de novo GLI2 variant (p.Ala551Thr) was identified in an individual with syndromic craniosynostosis (PMID:31292255).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.128 FUZ Achchuthan Shanmugasundram gene: FUZ was added
gene: FUZ was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FUZ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUZ were set to 34719684; 36980886
Phenotypes for gene: FUZ were set to craniosynostosis, MONDO:0015469
Review for gene: FUZ was set to RED
Added comment: A pair of monozygotic twins were described with craniosynostosis and a novel variant in FUZ (c.851G>C; p.Arg284Pro) (PMID:34719684).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.127 FTO Achchuthan Shanmugasundram gene: FTO was added
gene: FTO was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to 26697951; 36980886
Phenotypes for gene: FTO were set to craniosynostosis, MONDO:0015469
Review for gene: FTO was set to RED
Added comment: A homozygous variant in FTO (c.956G>A; p.Arg322Gln) was described in one individual with multiple malformation syndrome, which included craniosynostosis. Craniosynostosis is not a consistent feature of variants in FTO (PMID:26697951).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.126 FOXO1 Achchuthan Shanmugasundram gene: FOXO1 was added
gene: FOXO1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FOXO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXO1 were set to 35997807; 36980886
Phenotypes for gene: FOXO1 were set to craniosynostosis, MONDO:0015469
Review for gene: FOXO1 was set to RED
Added comment: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Arg180Trp) was identified in FOXO1. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.125 FOXP2 Achchuthan Shanmugasundram gene: FOXP2 was added
gene: FOXP2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FOXP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP2 were set to 35080095; 36980886
Phenotypes for gene: FOXP2 were set to craniosynostosis, MONDO:0015469
Review for gene: FOXP2 was set to RED
Added comment: A familial variant in FOXP2 (c.484del; p.Gln162fs) was identified in individuals with developmental delay, hypermetropia, orofacial dyspraxia and sagittal craniosynostosis. The variant is absent from gnomAD (PMID:35080095)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.124 FOXP1 Achchuthan Shanmugasundram gene: FOXP1 was added
gene: FOXP1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FOXP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP1 were set to 29330474; 36980886
Phenotypes for gene: FOXP1 were set to craniosynostosis, MONDO:0015469
Review for gene: FOXP1 was set to RED
Added comment: Whole exome sequencing identified a de novo splicing variant in FOXP1 (c.1428+1 G>A; p.Ala450GLyfs*13) in a patient with syndromic intellectual disability and trigonocephaly (PMID:29330474).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram changed review comment from: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).

Craniosynostosis has been recorded as part of the phenotype in OMIM (MIM #617425)
Sources: Literature; to: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).

Craniosynostosis has been recorded as part of the phenotype in OMIM (MIM #617425).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram changed review comment from: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).
Sources: Literature; to: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).

Craniosynostosis has been recorded as part of the phenotype in OMIM (MIM #617425)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram edited their review of gene: EXTL3: Changed phenotypes to: Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram Phenotypes for gene: EXTL3 were changed from craniosynostosis, MONDO:0015469 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.122 EXTL3 Achchuthan Shanmugasundram gene: EXTL3 was added
gene: EXTL3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: EXTL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXTL3 were set to 35080095; 36980886
Phenotypes for gene: EXTL3 were set to craniosynostosis, MONDO:0015469
Review for gene: EXTL3 was set to RED
Added comment: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.121 EIF5A Achchuthan Shanmugasundram gene: EIF5A was added
gene: EIF5A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EIF5A were set to 36118902; 36980886
Phenotypes for gene: EIF5A were set to craniosynostosis, MONDO:0015469
Review for gene: EIF5A was set to RED
Added comment: An intronic variant was identified in EIF5A (c.271-1G>C) within the Chinese cohort in a patient with metopic synostosis (PMID:36118902).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.120 EHMT1 Achchuthan Shanmugasundram gene: EHMT1 was added
gene: EHMT1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: EHMT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EHMT1 were set to 33288889; 36980886
Phenotypes for gene: EHMT1 were set to craniosynostosis, MONDO:0015469
Review for gene: EHMT1 was set to RED
Added comment: A de novo splicing variant was identified in EHMT1 (c.2018+1G>C) within the Norwegian cohort with syndromic craniosynostosis (PMID:33288889).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.119 DVL3 Achchuthan Shanmugasundram gene: DVL3 was added
gene: DVL3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: DVL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DVL3 were set to 28808027; 36980886
Phenotypes for gene: DVL3 were set to craniosynostosis, MONDO:0015469
Review for gene: DVL3 was set to RED
Added comment: An individual was described with sagittal synostosis and a de novo variant in DVL3 (p.Gly327fs*) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram changed review comment from: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733).

Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465).

A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G; p.(?) (PMID:32530565).
Sources: Literature; to: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733).

Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465).

A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G (PMID:32530565).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram Classified gene: DDX3X as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are five unrelated cases reported with DDX3X variants and likely craniosynostosis, only two are radiologically confirmed cases of craniosynostosis. Hence, this gene should be rated amber.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram Gene: ddx3x has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.117 DDX3X Achchuthan Shanmugasundram Phenotypes for gene: DDX3X were changed from craniosynostosis, MONDO:0015469 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.116 DDX3X Achchuthan Shanmugasundram edited their review of gene: DDX3X: Changed phenotypes to: Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.116 DDX3X Achchuthan Shanmugasundram gene: DDX3X was added
gene: DDX3X was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: DDX3X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: DDX3X were set to 30936465; 32530565; 33789733; 36980886
Phenotypes for gene: DDX3X were set to craniosynostosis, MONDO:0015469
Review for gene: DDX3X was set to AMBER
Added comment: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733).

Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465).

A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G; p.(?) (PMID:32530565).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.115 CTNNA1 Achchuthan Shanmugasundram gene: CTNNA1 was added
gene: CTNNA1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CTNNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNNA1 were set to 31292255; 36980886
Phenotypes for gene: CTNNA1 were set to craniosynostosis, MONDO:0015469
Review for gene: CTNNA1 was set to RED
Added comment: A de novo insertion (p.Val374_375ins) was identified in an individual from a screen of patients with syndromic craniosynostosis. This patient had sagittal craniosynostosis (PMID:31292255).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.114 COL11A1 Achchuthan Shanmugasundram gene: COL11A1 was added
gene: COL11A1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: COL11A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COL11A1 were set to 34429528; 36980886
Phenotypes for gene: COL11A1 were set to craniosynostosis, MONDO:0015469
Review for gene: COL11A1 was set to RED
Added comment: A de novo loss of function variant (c.2852+5G>A) was identified in an individual with craniosynostosis and a hearing impairment from the UK 100k genomes project (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.113 CHD3 Achchuthan Shanmugasundram gene: CHD3 was added
gene: CHD3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CHD3 were set to 30397230; 36980886
Phenotypes for gene: CHD3 were set to craniosynostosis, MONDO:0015469
Review for gene: CHD3 was set to RED
Added comment: One of 35 individuals identified with Snijders Blok Campeau syndrome (neurodevelopmental disorder, macrocephaly and impaired speech and language) and with monoallelic variants in CHD3 gene (c.3482A>G; p.His1161Arg) presented with sagittal synostosis (PMID:30397230).

In addition, one of 28 patients with sequence variants (c.52_53inv; p.Ser18Glu) in the DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes./
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.112 CDK8 Achchuthan Shanmugasundram gene: CDK8 was added
gene: CDK8 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDK8 were set to 30905399; 36980886
Phenotypes for gene: CDK8 were set to craniosynostosis, MONDO:0015469
Review for gene: CDK8 was set to RED
Added comment: Metopic synostosis was described in one individual out of 12 reported with variants in CDK8 from PMID:30905399. This individual harboured a de novo c.88G>A (p.Gly30Ser) variant.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.111 CACNA1E Achchuthan Shanmugasundram Phenotypes for gene: CACNA1E were changed from crannieynostosis, MONDO:0015469s to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.110 CACNA1E Achchuthan Shanmugasundram edited their review of gene: CACNA1E: Changed phenotypes to: craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.110 CACNA1E Achchuthan Shanmugasundram gene: CACNA1E was added
gene: CACNA1E was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CACNA1E were set to 32530565; 36980886
Phenotypes for gene: CACNA1E were set to crannieynostosis, MONDO:0015469s
Review for gene: CACNA1E was set to RED
Added comment: A heterozygous splice variant (c.3674+5A>G) was identified in an individual from a cohort of patients with trigonocephaly (PMID:32530565).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.109 BRWD3 Achchuthan Shanmugasundram changed review comment from: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes.
Sources: Literature; to: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene (p.Gly707Val) from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.109 BRWD3 Achchuthan Shanmugasundram Phenotypes for gene: BRWD3 were changed from to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.108 BRWD3 Achchuthan Shanmugasundram edited their review of gene: BRWD3: Changed phenotypes to: craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.108 BRWD3 Achchuthan Shanmugasundram gene: BRWD3 was added
gene: BRWD3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: BRWD3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: BRWD3 were set to 34429528; 36980886
Review for gene: BRWD3 was set to RED
Added comment: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.107 AXIN1 Achchuthan Shanmugasundram gene: AXIN1 was added
gene: AXIN1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: AXIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AXIN1 were set to 28808027; 36980886
Phenotypes for gene: AXIN1 were set to craniosynostosis, MONDO:0015469
Review for gene: AXIN1 was set to RED
Added comment: PMID:28808027 reported an individual with sagittal synostosis and a de novo heterozygous variant in AXIN1 gene.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.106 ARAP3 Achchuthan Shanmugasundram gene: ARAP3 was added
gene: ARAP3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARAP3 were set to 28808027; 36980886
Phenotypes for gene: ARAP3 were set to craniosynostosis, MONDO:0015469
Review for gene: ARAP3 was set to RED
Added comment: PMID:28808027 reported an individual identified with a de novo variant in ARAP3 (IVS6+1delGT) and presenting with metopic synostosis. As there is only one case reported so far, this gene should be rated red.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.105 ANKH Achchuthan Shanmugasundram Classified gene: ANKH as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.105 ANKH Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two cases reported in total with craniosynostosis. Hence, this gene can be rated amber.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.105 ANKH Achchuthan Shanmugasundram Gene: ankh has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.104 ANKH Achchuthan Shanmugasundram gene: ANKH was added
gene: ANKH was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ANKH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ANKH were set to 36118902; 36980886
Phenotypes for gene: ANKH were set to Craniometaphyseal dysplasia, OMIM:123000; craniosynostosis, MONDO:0015469
Review for gene: ANKH was set to AMBER
Added comment: PMID:36118902 reported a single patient with variant in ANKH (c.1129_1132delinsC; p.Phe377del) from a Chinese cohort with syndromic bicoronal and sagittal synostosis. This variant is reported as pathogenic for craniometaphyseal dysplasia in ClinVar and is absent from gnomAD v.2.1.1.

DECIPHER database (https://www.deciphergenomics.org) reported craniosynostosis as one of the clinical presentations in a single patient with heterozygous sequence variant (c.559C​>T; p.Arg187Trp) in ANKH gene. This variant was reported as likely pathogenic.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.103 ACVRL1 Achchuthan Shanmugasundram changed review comment from: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Val228Ile) in was identified in ACVRL1. Hence, this gene should be added with a red rating.
Sources: Literature; to: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Val228Ile) was identified in ACVRL1. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.103 ACVR2A Achchuthan Shanmugasundram gene: ACVR2A was added
gene: ACVR2A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ACVR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACVR2A were set to 35997807; 36980886
Phenotypes for gene: ACVR2A were set to craniosynostosis, MONDO:0015469
Review for gene: ACVR2A was set to RED
Added comment: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Thr63Ala) was identified in ACVR2A. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.102 ACVRL1 Achchuthan Shanmugasundram Phenotypes for gene: ACVRL1 were changed from to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.101 ACVRL1 Achchuthan Shanmugasundram edited their review of gene: ACVRL1: Changed phenotypes to: craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.101 ACVRL1 Achchuthan Shanmugasundram gene: ACVRL1 was added
gene: ACVRL1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ACVRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACVRL1 were set to 35997807; 36980886
Review for gene: ACVRL1 was set to RED
Added comment: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Val228Ile) in was identified in ACVRL1. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.100 ABCC9 Achchuthan Shanmugasundram changed review comment from: PMID:24352916 reported a Japanese family with Cantu syndrome, of which the boy had bicoronal synostosis, which was absent in the father. This gene should only be rated red as there is only one case reported so far.; to: PMID:24352916 reported a Japanese family with Cantu syndrome, of which the boy had bicoronal synostosis, which was absent in the father. Craniosynostosis has not previously been reported as part of Cantu syndrome. This gene should only be rated red as there is only one case reported so far.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.100 ABCC9 Achchuthan Shanmugasundram Publications for gene: ABCC9 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.99 ABCC9 Achchuthan Shanmugasundram Mode of inheritance for gene: ABCC9 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.98 ABCC9 Achchuthan Shanmugasundram reviewed gene: ABCC9: Rating: RED; Mode of pathogenicity: None; Publications: 24352916, 36980886; Phenotypes: Hypertrichotic osteochondrodysplasia (Cantu syndrome), OMIM: 239850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.98 ADAMTSL4 Eleanor Williams Mode of inheritance for gene: ADAMTSL4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.97 SMAD3 Achchuthan Shanmugasundram Publications for gene: SMAD3 were set to 20301312; 29392890; 31569402; 32935439
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.96 SMAD3 Achchuthan Shanmugasundram edited their review of gene: SMAD3: Changed publications to: 29392890, 31569402, 32935439, 36980886; Changed phenotypes to: Loeys-Dietz syndrome 3, OMIM:613795
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.96 SMAD3 Achchuthan Shanmugasundram changed review comment from: PMID:29392890 - It has been reviewed in this publication that craniosynostosis has only been reported once in a SMAD3 patient. But, no reference was given.

PMID:31569402 - Dolichocephaly has been reported in patients. However, it is not clear whether craniosynostosis has been present in these cases.

PMID:32935439 - One case of LDS with biallelic variants presented with craniosynostosis.

PMID:36980886 - one craniosynostosi case with splicing variant in SMAD3 from the cohort of 617 individuals.

This gene has been associated with LDS in OMIM (MIM #613795) and Gene2Phenotype (with 'definitive' rating in DD panel). However, craniosynostosis was not reported as part of phenotypes in OMIM.; to: PMID:29392890 - It has been reviewed in this publication that craniosynostosis has only been reported once in a SMAD3 patient. But, no reference was given.

PMID:31569402 - Dolichocephaly has been reported in patients. However, it is not clear whether craniosynostosis has been present in these cases.

PMID:32935439 - One case of LDS with biallelic variants presented with craniosynostosis.

PMID:36980886 - one craniosynostosi case with splicing variant in SMAD3 from the cohort of 617 individuals.

This gene has been associated with LDS in OMIM (MIM #613795) and Gene2Phenotype (with 'definitive' rating in DD panel). However, craniosynostosis was not reported as part of this phenotype in OMIM.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.96 SMAD3 Achchuthan Shanmugasundram reviewed gene: SMAD3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.96 AXIN2 Achchuthan Shanmugasundram Phenotypes for gene: AXIN2 were changed from Oligodontia-colorectal cancer syndrome, OMIM:608615 to Oligodontia-colorectal cancer syndrome, OMIM:608615; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.95 AXIN2 Achchuthan Shanmugasundram Publications for gene: AXIN2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.94 AXIN2 Achchuthan Shanmugasundram Mode of inheritance for gene: AXIN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.93 AXIN2 Achchuthan Shanmugasundram Classified gene: AXIN2 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.93 AXIN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is one case and supporting evidence from mouse models. Hence, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.93 AXIN2 Achchuthan Shanmugasundram Gene: axin2 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.92 AXIN2 Achchuthan Shanmugasundram reviewed gene: AXIN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 15790973, 30088857, 30976280, 34134783; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.92 SH3PXD2B Achchuthan Shanmugasundram commented on gene: SH3PXD2B: PMID:23140272 reported a family of three siblings with homozygous variants in SH3PXD2B and two of them presented with craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.92 SH3PXD2B Achchuthan Shanmugasundram reviewed gene: SH3PXD2B: Rating: RED; Mode of pathogenicity: None; Publications: 23140272; Phenotypes: Frank-ter Haar syndrome, OMIM:249420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.92 SPRY1 Achchuthan Shanmugasundram Classified gene: SPRY1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.92 SPRY1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is one case and supporting functional evidence. Hence, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.92 SPRY1 Achchuthan Shanmugasundram Gene: spry1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.91 SPRY1 Achchuthan Shanmugasundram Phenotypes for gene: SPRY1 were changed from to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.90 SPRY1 Achchuthan Shanmugasundram Publications for gene: SPRY1 were set to PMID36543535
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.89 SPRY1 Achchuthan Shanmugasundram Publications for gene: SPRY1 were set to PMID36543535
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.89 SPRY1 Achchuthan Shanmugasundram Publications for gene: SPRY1 were set to PMID: 36543535
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.88 SPRY1 Achchuthan Shanmugasundram Publications for gene: SPRY1 were set to PMID: 36543535
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 SPRY1 Achchuthan Shanmugasundram reviewed gene: SPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36543535; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 RSPRY1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence (3 unrelated cases) for this gene to be promoted to GREEN rating in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 RSPRY1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616723) and Gene2Phenotype (with 'strong' rating in the DD panel).; to: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616723) and Gene2Phenotype (with 'strong' rating in the DD panel).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 RSPRY1 Achchuthan Shanmugasundram Classified gene: RSPRY1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 RSPRY1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 RSPRY1 Achchuthan Shanmugasundram Gene: rspry1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.86 RSPRY1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341.; to: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616723) and Gene2Phenotype (with 'strong' rating in the DD panel).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.86 RSPRY1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: RSPRY1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.86 RSPRY1 Achchuthan Shanmugasundram Phenotypes for gene: RSPRY1 were changed from to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.85 RSPRY1 Achchuthan Shanmugasundram Publications for gene: RSPRY1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.84 RSPRY1 Achchuthan Shanmugasundram Mode of inheritance for gene: RSPRY1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.83 RSPRY1 Achchuthan Shanmugasundram Classified gene: RSPRY1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.83 RSPRY1 Achchuthan Shanmugasundram Gene: rspry1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 RSPRY1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases.; to: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 RSPRY1 Achchuthan Shanmugasundram edited their review of gene: RSPRY1: Changed rating: GREEN
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 RSPRY1 Achchuthan Shanmugasundram reviewed gene: RSPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365341, 30063090; Phenotypes: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 OGT Achchuthan Shanmugasundram Classified gene: OGT as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 OGT Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are only two cases reported so far, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 OGT Achchuthan Shanmugasundram Gene: ogt has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.81 OGT Achchuthan Shanmugasundram Mode of inheritance for gene: OGT was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.80 OGT Achchuthan Shanmugasundram Publications for gene: OGT were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.79 OGT Achchuthan Shanmugasundram Phenotypes for gene: OGT were changed from to Intellectual developmental disorder, X-linked 106, OMIM:300997
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.78 OGT Achchuthan Shanmugasundram reviewed gene: OGT: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565, 34429528; Phenotypes: Intellectual developmental disorder, X-linked 106, OMIM:300997; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.78 IRX5 Achchuthan Shanmugasundram changed review comment from: PMID:22581230 - One family with three cases presenting with craniosynostosis.
PMID:29168297 - one case with craniosynostosis.; to: PMID:22581230 - One family with three cases presenting with craniosynostosis.
PMID:29168297 - one case with craniosynostosis.

This gene has been associated with relevant phenotypes in both OMIM (MIM #611174) and Gene2Phenotype (with 'strong' rating in the DD panel).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.78 IRX5 Achchuthan Shanmugasundram Classified gene: IRX5 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.78 IRX5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are only two unrelated cases, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.78 IRX5 Achchuthan Shanmugasundram Gene: irx5 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.77 IRX5 Achchuthan Shanmugasundram Phenotypes for gene: IRX5 were changed from Hamamy syndrome to Hamamy syndrome, OMIM:611174
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.76 IRX5 Achchuthan Shanmugasundram Publications for gene: IRX5 were set to 22581230
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.75 IRX5 Achchuthan Shanmugasundram edited their review of gene: IRX5: Changed rating: AMBER
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.75 IRX5 Achchuthan Shanmugasundram reviewed gene: IRX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22581230, 29168297; Phenotypes: Hamamy syndrome, OMIM:611174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.75 IFT43 Achchuthan Shanmugasundram Publications for gene: IFT43 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.74 IFT43 Achchuthan Shanmugasundram Mode of inheritance for gene: IFT43 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.73 IFT43 Achchuthan Shanmugasundram reviewed gene: IFT43: Rating: RED; Mode of pathogenicity: None; Publications: 21378380; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.73 IFT140 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: IFT140.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.73 IFT140 Achchuthan Shanmugasundram Publications for gene: IFT140 were set to 27874174; 28288023; 32007091
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.72 IFT140 Achchuthan Shanmugasundram Classified gene: IFT140 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.72 IFT140 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (at least 3 cases) for this gene to be promoted to GREEN rating in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.72 IFT140 Achchuthan Shanmugasundram Gene: ift140 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.71 IFT140 Achchuthan Shanmugasundram edited their review of gene: IFT140: Added comment: PMID:22503633 - two cases from a single family with craniosynostosis, scaphocephaly and facial dysmorphy.
PMID:27874174 - single case with trigonocephaly and additional ciliopathy-related clinical features.
PMID:28288023 - single case with evolving craniofacial phenotype, striking brachydactyly and sensenbrenner syndromeand it was not clear if craniosynostosis was radiologically confirmed (as reviewed by Rebecca Tooze).
PMID:32007091 - single case with craniosynostosis and dolichocephaly.; Changed rating: GREEN; Changed publications to: 22503633, 27874174, 28288023, 32007091
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.71 IFT140 Achchuthan Shanmugasundram Phenotypes for gene: IFT140 were changed from hort-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920 to Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.70 IFT140 Achchuthan Shanmugasundram Phenotypes for gene: IFT140 were changed from Short-rib thoracic dysplasia with or without polydactyly; asphyxiating thoracic dysplasia (ATD,Jeune) to hort-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.69 IFT140 Achchuthan Shanmugasundram Publications for gene: IFT140 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.68 IFT140 Achchuthan Shanmugasundram Mode of inheritance for gene: IFT140 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.67 IFT140 Achchuthan Shanmugasundram reviewed gene: IFT140: Rating: AMBER; Mode of pathogenicity: None; Publications: 27874174, 28288023, 32007091; Phenotypes: Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.67 GPC3 Achchuthan Shanmugasundram Classified gene: GPC3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.67 GPC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: The evidence is not sufficient for green rating and should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.67 GPC3 Achchuthan Shanmugasundram Gene: gpc3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.66 GPC3 Achchuthan Shanmugasundram Phenotypes for gene: GPC3 were changed from Simpson-Golabi-Behmel syndrome to Simpson-Golabi-Behmel syndrome, type 1, OMIM:312870
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.65 GPC3 Achchuthan Shanmugasundram Publications for gene: GPC3 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.64 GPC3 Achchuthan Shanmugasundram Mode of inheritance for gene: GPC3 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.63 GPC3 Achchuthan Shanmugasundram commented on gene: GPC3: In addition to cases reviewed by Rebecca Tooze (University of Oxford), PMID:19372699 reported a prenatal case identified with hemizygous deletion in GPC3 gene (c.194-206del/ p.Cys65fs) and diagnosed with polyhydramnios, macrosomia, macroglossia, left-sided cleft lip and palate, nephromegaly, hepatosplenomegaly as well as an abnormal skull shape due to lamboid craniosynostosis via ultrasound at 30 weeks off gestation.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.63 GPC3 Achchuthan Shanmugasundram edited their review of gene: GPC3: Changed publications to: 19372699, 24115482, 25804025, 34429528
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.63 GPC3 Achchuthan Shanmugasundram reviewed gene: GPC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 24115482, 25804025, 34429528; Phenotypes: Simpson-Golabi-Behmel syndrome, type 1, OMIM:312870; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.63 FREM1 Achchuthan Shanmugasundram Classified gene: FREM1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.63 FREM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are five cases with heterozygous variants in FREM1 gene associated with craniosynostosis/ trigonocephaly, there is also conflicting evidence suggesting there is no association of heterozygous variants in this gene with craniosynostosis. Hence, this gene can only be rated AMBER with the current evidence.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.63 FREM1 Achchuthan Shanmugasundram Gene: frem1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.62 FREM1 Achchuthan Shanmugasundram Phenotypes for gene: FREM1 were changed from Manitoba oculotrichoanal syndrome; bifid nose; trigonocephaly to Trigonocephaly 2, OMIM:614485
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.61 FREM1 Achchuthan Shanmugasundram Publications for gene: FREM1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.60 FREM1 Achchuthan Shanmugasundram Mode of inheritance for gene: FREM1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.59 FREM1 Achchuthan Shanmugasundram reviewed gene: FREM1: Rating: ; Mode of pathogenicity: None; Publications: 21931569, 33038106, 33288889, 33937142; Phenotypes: Trigonocephaly 2, OMIM:614485; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.59 DPH1 Achchuthan Shanmugasundram changed review comment from: Sagittal craniosynostosis was reported in one of the four North American patients identified with biallelic variants (c.17T>A/ p.Met6Lys) in DPH1 gene in PMID:26220823.

A family of two affected siblings identified with recessive variants (c.374 T > C/ p.Leu125Pro) in DPH1 presented with metopic synostosis.; to: Sagittal craniosynostosis was reported in one of the four North American patients identified with biallelic variants (c.17T>A/ p.Met6Lys) in DPH1 gene in PMID:26220823.

A family of two affected siblings identified with recessive variants (c.374 T > C/ p.Leu125Pro) in DPH1 presented with metopic synostosis.

This gene has been associated with relevant phenotypes in OMIM (MIM #616901).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.59 DPH1 Achchuthan Shanmugasundram Phenotypes for gene: DPH1 were changed from to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.58 DPH1 Achchuthan Shanmugasundram Publications for gene: DPH1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.57 DPH1 Achchuthan Shanmugasundram Classified gene: DPH1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.57 DPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are only two unrelated cases. Hence, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.57 DPH1 Achchuthan Shanmugasundram Gene: dph1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.56 DPH1 Achchuthan Shanmugasundram reviewed gene: DPH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26220823, 30877278; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.56 DPF2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two cases of confirmed craniosynostosis with the same variant (p.Asp346Gly). Although there is a third case with trigonocephaly harbouring a different variant (p.Asp340Glufs*12), craniosynostosis was not radiologically confirmed in this individual. Hence, this gene should be rated AMBER.; to: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two cases of confirmed craniosynostosis with the same variant (p.Asp346Gly). Although there is a third case with trigonocephaly harbouring a different variant (p.Asp340Glufs*12), craniosynostosis was not radiologically confirmed in this individual. Hence, this gene should be rated AMBER.

This gene has been associated with Coffin-Siris syndrome in both OMIM (MIM #618027) and Gene2Phenotype (with a 'strong' rating in the DD panel).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.56 DPF2 Achchuthan Shanmugasundram Publications for gene: DPF2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.55 DPF2 Achchuthan Shanmugasundram Classified gene: DPF2 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.55 DPF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two cases of confirmed craniosynostosis with the same variant (p.Asp346Gly). Although there is a third case with trigonocephaly harbouring a different variant (p.Asp340Glufs*12), craniosynostosis was not radiologically confirmed in this individual. Hence, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.55 DPF2 Achchuthan Shanmugasundram Gene: dpf2 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.54 DPF2 Achchuthan Shanmugasundram reviewed gene: DPF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29429572; Phenotypes: Coffin-Siris syndrome 7, OMIM:618027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.54 ASXL3 Achchuthan Shanmugasundram Classified gene: ASXL3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.54 ASXL3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are only two cases of craniosynostosis and craniosynostosis was not confirmed in the third case. Hence, this gene should be rated AMBER.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.54 ASXL3 Achchuthan Shanmugasundram Gene: asxl3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.53 ASXL3 Achchuthan Shanmugasundram Phenotypes for gene: ASXL3 were changed from to Bainbridge-Ropers syndrome, OMIM:615485; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.52 ASXL3 Achchuthan Shanmugasundram Publications for gene: ASXL3 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.51 ASXL3 Achchuthan Shanmugasundram reviewed gene: ASXL3: Rating: AMBER; Mode of pathogenicity: None; Publications: 24044690, 33288889; Phenotypes: Bainbridge-Ropers syndrome, OMIM:615485, craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.51 SOX6 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: SOX6.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.51 SOX6 Achchuthan Shanmugasundram Phenotypes for gene: SOX6 were changed from craniosynostosis to Tolchin-Le Caignec syndrome, OMIM:618971; craniosynostosis
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.50 SOX6 Achchuthan Shanmugasundram Publications for gene: SOX6 were set to 32442410; 16258006
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.49 SOX6 Achchuthan Shanmugasundram Mode of inheritance for gene: SOX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.48 SOX6 Achchuthan Shanmugasundram Classified gene: SOX6 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.48 SOX6 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence available (seven unrelated cases) for this gene to be promoted to GREEN rating in the next GMS update.

In addition, this gene has also been associated with relevant phenotypes in both OMIM (MIM #618971 ) and Gene2Phenotype (with 'strong' rating in the DD panel).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.48 SOX6 Achchuthan Shanmugasundram Gene: sox6 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.47 SOX6 Achchuthan Shanmugasundram reviewed gene: SOX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 16258006, 32442410, 36118902, 36980886; Phenotypes: Tolchin-Le Caignec syndrome, OMIM:618971; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.47 PRRX1 Achchuthan Shanmugasundram Classified gene: PRRX1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.47 PRRX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford) and reported in PMID:37154149, there is sufficient evidence for this gene to be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.47 PRRX1 Achchuthan Shanmugasundram Gene: prrx1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.46 PRRX1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: PRRX1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.46 PRRX1 Achchuthan Shanmugasundram Phenotypes for gene: PRRX1 were changed from craniosynostosis, various combinations of sutures to Agnathia-otocephaly complex, OMIM:202650; craniosynostosis, MONDO:0015469; craniosynostosis, various combinations of sutures
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.45 PRRX1 Achchuthan Shanmugasundram Publications for gene: PRRX1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.44 PRRX1 Achchuthan Shanmugasundram edited their review of gene: PRRX1: Added comment: PMID:37154149 reported 15 patients from 12 unrelated families presenting with craniosynostosis and were identified with heterozygous variants in PRRX1 gene, while three cases from three additional families had deletion (family 13: 61.5kb; family 14: 76kb; family 15: 10.5Mb deletion). These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%. These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation.; Changed phenotypes to: Agnathia-otocephaly complex, OMIM:202650, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.44 PRRX1 Achchuthan Shanmugasundram reviewed gene: PRRX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36980886, 37154149; Phenotypes: Agnathia-otocephaly complex, OMIM:202650; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.44 NFIX Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: NFIX.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.44 NFIX Achchuthan Shanmugasundram Classified gene: NFIX as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.44 NFIX Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence (4 unrelated cases) available for promotion of this gene to GREEN rating in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.44 NFIX Achchuthan Shanmugasundram Gene: nfix has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.43 NFIX Achchuthan Shanmugasundram Phenotypes for gene: NFIX were changed from Marshall-Smith syndrome to Malan syndrome, OMIM:614753; Marshall-Smith syndrome, OMIM:602535; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.42 NFIX Achchuthan Shanmugasundram edited their review of gene: NFIX: Changed phenotypes to: Malan syndrome, OMIM:614753, Marshall-Smith syndrome, OMIM:602535, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.42 NFIX Achchuthan Shanmugasundram Publications for gene: NFIX were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.41 NFIX Achchuthan Shanmugasundram Mode of inheritance for gene: NFIX was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.40 NFIX Achchuthan Shanmugasundram reviewed gene: NFIX: Rating: GREEN; Mode of pathogenicity: None; Publications: 33288889, 35997807; Phenotypes: Malan syndrome, OMIM:614753, Marshall-Smith syndrome, OMIM:602535; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.40 MAN2B1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: MAN2B1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.40 MAN2B1 Achchuthan Shanmugasundram Classified gene: MAN2B1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.40 MAN2B1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are three unrelated cases identified with biallelic variants in MAN2B1 gene presented with craniosynostosis, although there are several other cases identified with biallelic variants in MAN2B1, who did not present with craniosynostosis. As there are three unrelated cases with craniosynostosis, this gene can be promoted to GREEN rating in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.40 MAN2B1 Achchuthan Shanmugasundram Gene: man2b1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.39 MAN2B1 Achchuthan Shanmugasundram Phenotypes for gene: MAN2B1 were changed from to Mannosidosis, alpha-, types I and II, OMIM:248500
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.38 MAN2B1 Achchuthan Shanmugasundram Publications for gene: MAN2B1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.37 MAN2B1 Achchuthan Shanmugasundram reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33288889, 34429528, 35242565; Phenotypes: Mannosidosis, alpha-, types I and II, OMIM:248500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.37 KAT6B Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: KAT6B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.37 KAT6B Achchuthan Shanmugasundram Classified gene: KAT6B as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.37 KAT6B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are three unrelated cases to support the promotion of this gene to GREEN rating in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.37 KAT6B Achchuthan Shanmugasundram Gene: kat6b has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.36 KAT6B Achchuthan Shanmugasundram Phenotypes for gene: KAT6B were changed from KAT6B-related disorders to KAT6B-related disorders; Genitopatellar syndrome, OMIM:606170
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.35 KAT6B Achchuthan Shanmugasundram Publications for gene: KAT6B were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.34 KAT6B Achchuthan Shanmugasundram Mode of inheritance for gene: KAT6B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.33 KAT6B Achchuthan Shanmugasundram reviewed gene: KAT6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28696035, 33288889; Phenotypes: Genitopatellar syndrome, OMIM:606170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.33 IL6ST Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: IL6ST.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.33 IL6ST Achchuthan Shanmugasundram Classified gene: IL6ST as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.33 IL6ST Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two unrelated cases and supporting functional studies in mice. Hence, this gene can be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.33 IL6ST Achchuthan Shanmugasundram Gene: il6st has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.32 IL6ST Achchuthan Shanmugasundram Phenotypes for gene: IL6ST were changed from to Hyper-IgE recurrent infection syndrome 4B, autosomal recessive, OMIM:618523
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.31 IL6ST Achchuthan Shanmugasundram Publications for gene: IL6ST were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.30 IL6ST Achchuthan Shanmugasundram reviewed gene: IL6ST: Rating: GREEN; Mode of pathogenicity: None; Publications: 28747427, 32566365; Phenotypes: Hyper-IgE recurrent infection syndrome 4B, autosomal recessive, OMIM:618523; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.30 FGF9 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: FGF9.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.30 FGF9 Achchuthan Shanmugasundram Classified gene: FGF9 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.30 FGF9 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two unrelated cases and supporting functional evidence available for this gene. Hence, it can be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.30 FGF9 Achchuthan Shanmugasundram Gene: fgf9 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.29 FGF9 Achchuthan Shanmugasundram Phenotypes for gene: FGF9 were changed from to Multiple synostoses syndrome 3, OMIM:612961
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.28 FGF9 Achchuthan Shanmugasundram Publications for gene: FGF9 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.27 FGF9 Achchuthan Shanmugasundram Mode of inheritance for gene: FGF9 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.26 FGF9 Achchuthan Shanmugasundram reviewed gene: FGF9: Rating: GREEN; Mode of pathogenicity: None; Publications: 12140681, 19589401, 28730625; Phenotypes: Multiple synostoses syndrome 3, OMIM:612961; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.26 FBXO11 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: FBXO11.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.26 FBXO11 Achchuthan Shanmugasundram Classified gene: FBXO11 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.26 FBXO11 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are three unrelated cases reported with variants in this gene and craniosynostosis. Hence, this gene can be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.26 FBXO11 Achchuthan Shanmugasundram Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.25 FBXO11 Achchuthan Shanmugasundram Phenotypes for gene: FBXO11 were changed from to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:618089
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.24 FBXO11 Achchuthan Shanmugasundram Publications for gene: FBXO11 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.23 FBXO11 Achchuthan Shanmugasundram reviewed gene: FBXO11: Rating: GREEN; Mode of pathogenicity: None; Publications: 30057029, 34429528; Phenotypes: Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:618089; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.23 FBN1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: FBN1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.23 FBN1 Achchuthan Shanmugasundram Classified gene: FBN1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.23 FBN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence (>3 unrelated cases) for this gene to be promoted to GREEN in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.23 FBN1 Achchuthan Shanmugasundram Gene: fbn1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.22 FBN1 Achchuthan Shanmugasundram Phenotypes for gene: FBN1 were changed from Marfan syndrome to Marfan syndrome, OMIM:154700; Marfan lipodystrophy syndrome, OMIM:616914; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.21 FBN1 Achchuthan Shanmugasundram Publications for gene: FBN1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.20 FBN1 Achchuthan Shanmugasundram Mode of inheritance for gene: FBN1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 FBN1 Achchuthan Shanmugasundram changed review comment from: PMID:16596670 reported two cases that had heterozygous FBN1 variants. One had scaphocephaly with indistinct coronal sutures and partial sagittal synostosis. Second had plagiocephaly with patent coronal, lambdoid and sagittal sutures. A third case had FBN1 deletion with dolichocephaly.

PMID:24039054 reported a girl with severe congenital lipodystrophy and a neonatal progeroid appearance. She exhibited an accelerated growth in height with a discrepant poor weight gain and a characteristic facial appearance with craniosynostosis. She was identified with the variant c.8175_8182del8bp/ p.Arg2726Glufs*9 in FBN1 gene.

PMID:27884935 reported the identification of a de novo splice variant in FBN1gene (c.8226+5G>A) in a patient with craniosynostosis.

PMID:29168297 reported two probands with variants in FBN1 (proband 1: c.1169C>T/ p.(Ser390Phe) & c.8149G>A/ p.(Glu2717Lys); proband 2: c.7661G>A/ p.(Arg2554Gln)) presenting with me topic (proband 1) and sagittal (proband 2) craniosynostosis.

PMID:31754721 reported a patient with Marfan syndrome identified with c.4096G>A/ p.(Glu1366Lys) variant in FBN1 gene. This patient presented with sagittal and bilambdoidal craniosynostosis.; to: PMID:16596670 reported two cases that had heterozygous FBN1 variants. One had scaphocephaly with indistinct coronal sutures and partial sagittal synostosis. Second had plagiocephaly with patent coronal, lambdoid and sagittal sutures. A third case had FBN1 deletion with dolichocephaly.

PMID:24039054 reported a girl with severe congenital lipodystrophy and a neonatal progeroid appearance. She exhibited an accelerated growth in height with a discrepant poor weight gain and a characteristic facial appearance with craniosynostosis. She was identified with the variant c.8175_8182del8bp/ p.Arg2726Glufs*9 in FBN1 gene.

PMID:27884935 reported the identification of a de novo splice variant in FBN1gene (c.8226+5G>A) in a patient with craniosynostosis.

PMID:29168297 reported two probands with variants in FBN1 (proband 1: c.1169C>T/ p.(Ser390Phe) & c.8149G>A/ p.(Glu2717Lys); proband 2: c.7661G>A/ p.(Arg2554Gln)) presenting with me topic (proband 1) and sagittal (proband 2) craniosynostosis.

PMID:31754721 reported a patient with Marfan syndrome identified with c.4096G>A/ p.(Glu1366Lys) variant in FBN1 gene. This patient presented with sagittal and bilambdoidal craniosynostosis.

This gene has been associated with relevant phenotypes in both OMIM and Gene2Phenotype databases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 FBN1 Achchuthan Shanmugasundram edited their review of gene: FBN1: Changed phenotypes to: Marfan syndrome, OMIM:154700, Marfan lipodystrophy syndrome, OMIM:616914, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 FBN1 Achchuthan Shanmugasundram reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16596670, 24039054, 27884935, 29168297, 31754721; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 BCL11B Achchuthan Shanmugasundram Tag Q2_21_NHS_review was removed from gene: BCL11B.
Tag Q2_23_NHS_review tag was added to gene: BCL11B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 CDK13 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: CDK13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 CDK13 Achchuthan Shanmugasundram Classified gene: CDK13 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 CDK13 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are four unrelated cases identified with heterozygous variants in CDK13 gene and presenting with craniosynostosis. Hence, this gene can be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.19 CDK13 Achchuthan Shanmugasundram Gene: cdk13 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.18 CDK13 Achchuthan Shanmugasundram Publications for gene: CDK13 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.17 CDK13 Achchuthan Shanmugasundram Phenotypes for gene: CDK13 were changed from to Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, OMIM:617360; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.16 CDK13 Achchuthan Shanmugasundram reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: None; Publications: 28807008, 33288889, 34429528; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, OMIM:617360, craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.16 BCL11B Eleanor Williams Tag Q2_21_NHS_review tag was added to gene: BCL11B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.16 BCL11B Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: BCL11B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.16 BCL11B Achchuthan Shanmugasundram Phenotypes for gene: BCL11B were changed from Craniosynostosis and global developmental delay to Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, OMIM:618092; Craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.15 BCL11B Achchuthan Shanmugasundram Publications for gene: BCL11B were set to 36275064; 310673176; 34900871; 36512050; 36470856
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.14 BCL11B Achchuthan Shanmugasundram Classified gene: BCL11B as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.14 BCL11B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Rebecca Tooze (University of Oxford), there is sufficient number of cases (both published and unpublished) and supporting functional evidence for this gene to be promoted to GREEN in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.14 BCL11B Achchuthan Shanmugasundram Gene: bcl11b has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.13 BCL11B Achchuthan Shanmugasundram reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31067316, 34900871, 36275064, 36470856, 36512050, 36980886; Phenotypes: Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, OMIM:618092, Craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.13 ARID1B Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: ARID1B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.13 ARID1B Achchuthan Shanmugasundram Phenotypes for gene: ARID1B were changed from Coffin-Siris syndrome 1, OMIM:135900 to Coffin-Siris syndrome 1, OMIM:135900
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.12 ARID1B Achchuthan Shanmugasundram Phenotypes for gene: ARID1B were changed from to Coffin-Siris syndrome 1, OMIM:135900
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.11 ARID1B Achchuthan Shanmugasundram Publications for gene: ARID1B were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.10 ARID1B Achchuthan Shanmugasundram Classified gene: ARID1B as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.10 ARID1B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence (>3 unrelated cases) for this gene to be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.10 ARID1B Achchuthan Shanmugasundram Gene: arid1b has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.9 ARID1B Achchuthan Shanmugasundram reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 27474218, 32530565, 34429528, 36118902, 36980886; Phenotypes: Coffin-Siris syndrome 1, OMIM:135900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.9 AHDC1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: AHDC1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.9 AHDC1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated cases of Xia-Gibbs syndrome reported with craniosynostosis as one of their clinical manifestations. Hence, this gene can be promoted to GREEN in the next major review.; to: Comment on list classification: There are three unrelated cases of Xia-Gibbs syndrome reported with craniosynostosis as one of their clinical manifestations and they all had different heterozygous variants. Hence, this gene can be promoted to GREEN in the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.9 AHDC1 Achchuthan Shanmugasundram Classified gene: AHDC1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.9 AHDC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases of Xia-Gibbs syndrome reported with craniosynostosis as one of their clinical manifestations. Hence, this gene can be promoted to GREEN in the next major review.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.9 AHDC1 Achchuthan Shanmugasundram Gene: ahdc1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.8 AHDC1 Achchuthan Shanmugasundram changed review comment from: PMID:27884935 reported whole exome and genome sequencing analysis in a cohort of patients with undiagnosed craniosynostosis and identified one patient with a de novo variant (c.2373_2374delTG/ p.Cys791fs*57) in AHDC1. In addition to bicoronal and metopic craniosynostosis, the patient also had moderate developmental delay and hoarse cry.

PMID:30152016 reported the clinical phenotypes of five patients diagnosed with AHDC1-related Xia-Gibbs syndrome. Out of these five cases, one patient presented with bicoronal craniosynostosis in addition to intellectual disability and speech and motor delay and harboured a different heterozygous variant in AHDC1 (c.2473C > T/ p.Gln825*).

PMID:30858058 reported a two-year-old girl with developmental delay, brain anomalies, laryngomalacia and craniosynostosis and she was identified with a heterozygous variant (c.4370 A>G/ p.Asp1457Gly) in AHDC1.; to: A subset of patients with Xia-Gibbs syndrome (MIM #615829) presented with craniosynostosis as part of their clinical phenotype.

PMID:27884935 reported whole exome and genome sequencing analysis in a cohort of patients with undiagnosed craniosynostosis and identified one patient with a de novo variant (c.2373_2374delTG/ p.Cys791fs*57) in AHDC1. In addition to bicoronal and metopic craniosynostosis, the patient also had moderate developmental delay and hoarse cry.

PMID:30152016 reported the clinical phenotypes of five patients diagnosed with AHDC1-related Xia-Gibbs syndrome. Out of these five cases, one patient presented with bicoronal craniosynostosis in addition to intellectual disability and speech and motor delay and harboured a different heterozygous variant in AHDC1 (c.2473C > T/ p.Gln825*).

PMID:30858058 reported a two-year-old girl with developmental delay, brain anomalies, laryngomalacia and craniosynostosis and she was identified with a heterozygous variant (c.4370 A>G/ p.Asp1457Gly) in AHDC1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.8 AHDC1 Achchuthan Shanmugasundram Mode of inheritance for gene: AHDC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.7 AHDC1 Achchuthan Shanmugasundram Publications for gene: AHDC1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.6 AHDC1 Achchuthan Shanmugasundram Phenotypes for gene: AHDC1 were changed from Xia-Gibbs syndrome 615829 to Xia-Gibbs syndrome, OMIM:615829
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.5 AHDC1 Achchuthan Shanmugasundram reviewed gene: AHDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27884935, 30152016, 30858058; Phenotypes: Xia-Gibbs syndrome, OMIM:615829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.5 ADAMTSL4 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: ADAMTSL4.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.5 ADAMTSL4 Achchuthan Shanmugasundram Classified gene: ADAMTSL4 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.5 ADAMTSL4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN at the next GMS update.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.5 ADAMTSL4 Achchuthan Shanmugasundram Gene: adamtsl4 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.4 ADAMTSL4 Achchuthan Shanmugasundram Phenotypes for gene: ADAMTSL4 were changed from Ectopia lentis 225200/225100 to Ectopia lentis 225200/225100; craniosynostosis with ectopia lentis, MONDO:0011347
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.3 ADAMTSL4 Achchuthan Shanmugasundram Publications for gene: ADAMTSL4 were set to 10215540; 20702823; 22871183; 28642162; 35378950
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.2 ADAMTSL4 Achchuthan Shanmugasundram Publications for gene: ADAMTSL4 were set to 22871183; 20702823
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.1 ADAMTSL4 Achchuthan Shanmugasundram changed review comment from: PMID:20702823 reported 10 affected individuals from five unrelated Norwegian families with homozygous variants (c.767_786del/ p.Gln256Profs∗38) and they presented with ectopia lentis et pupillae. All these patients were surgically corrected for craniosynostosis.

PMID:22871183 reported a patient with right coronal synostosis and bilateral ectopia lentis, who harboured the same homozygous deletion variant. The proband's mother, father and one sibling are heterozygous carriers of the variant.

PMID:28642162 reported a Dutch family with monozygotic twins harbouring compound heterozygous variants (c.767_786del/ p.Gln256Profs∗38 & c.2254C > T/ p.Gln752∗) and both presented with craniosynostosis and ectopia lentis.

PMID:35378950 reported two unrelated families with craniosynostosis and ectopia lentis. Family 1’s proband is compound heterozygous (c.767_786del & c.2177 + 3_2177 + ) and family 2 has two homozygous affected siblings with c.767_786del, however the older sister did not have craniosynostosis (ectopia lentis only).; to: PMID:20702823 reported 10 affected individuals from five unrelated Norwegian families with homozygous variants (c.767_786del/ p.Gln256Profs∗38) and they presented with ectopia lentis et pupillae. All these patients were surgically corrected for craniosynostosis.

PMID:22871183 reported a patient with right coronal synostosis and bilateral ectopia lentis, who harboured the same homozygous deletion variant. The proband's mother, father and one sibling are heterozygous carriers of the variant.

PMID:28642162 reported a Dutch family with monozygotic twins harbouring compound heterozygous variants (c.767_786del/ p.Gln256Profs∗38 & c.2254C > T/ p.Gln752∗) and both presented with craniosynostosis and ectopia lentis.

PMID:35378950 reported two unrelated families with craniosynostosis and ectopia lentis. Family 1’s proband is compound heterozygous (c.767_786del & c.2177 + 3_2177 + ) and family 2 has two homozygous affected siblings with c.767_786del, however the older sister did not have craniosynostosis (ectopia lentis only).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.1 ADAMTSL4 Achchuthan Shanmugasundram reviewed gene: ADAMTSL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10215540, 20702823, 22871183, 28642162, 35378950; Phenotypes: craniosynostosis with ectopia lentis, MONDO:0011347; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.1 Catherine Snow Panel version 4.0 has been signed off on 2023-03-22
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.0 Catherine Snow promoted panel to version 4.0
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.5 Sarah Leigh Panel name changed from Craniosynostosis to Rare syndromic craniosynostosis or isolated multisuture synostosis
List of related panels changed from Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; R100 to Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; Craniosynostosis; R100
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 SPRY1 Rebecca Tooze gene: SPRY1 was added
gene: SPRY1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: SPRY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRY1 were set to PMID: 36543535
Review for gene: SPRY1 was set to AMBER
Added comment: • Single report of a homozygous loss of function variant (c.80T>A; p.(Leu27*)) in a patient with sagittal craniosynostosis, alongside hearing and kidney anomalies. Functional studies show complete absence of the protein and support variant pathogenicity (Tooze et al., 2022a). This is the first human description but there are available animal models showing the role of SPRY1 in craniofacial development.
• An individual was described with a heterozygous variant in SPRY1: p.(Gln6fs) (Timberlake et al., 2017), but evidence suggests that heterozygous loss-of-function variants are not pathogenic (see above reference).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 OGT Rebecca Tooze gene: OGT was added
gene: OGT was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: OGT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: OGT was set to AMBER
Added comment: • A de novo variant in OGT was identified within the 100kGP cohort: c.539A>G; p.(Tyr180Cys) (Hyder et al., 2021).
• An analysis of a cohort of patients with trigonocephaly identified a splicing variant in OGT: c.1947+5A>C. The patient displayed a delay in speech acquisition, hyperkinesia, sleep disorders and trigonocephaly (Suzuki et al., 2020).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 MAN2B1 Rebecca Tooze gene: MAN2B1 was added
gene: MAN2B1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: MAN2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: MAN2B1 was set to GREEN
Added comment: • A Norwegian study of patients with craniosynostosis identified a homozygous missense variant in MAN2B1: c.1055 T>C; p.(Leu352Pro) (Tønne et al., 2021).
• Compound heterozygous variant were identified through screening 114 families with craniosynostosis within the UK 100kGP: c.1830+1G>C; p.(?) and c.2248C>T; p.(Arg750Trp) (Hyder et al., 2021).
• One patient out of 12 with recessive variants in MAN2B1 was described with craniosynostosis: c.2245C>T; p.(Arg749Trp), and c.2355G>A; p.(Thr785*) (Lipiński et al., 2022).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 IL6ST Rebecca Tooze gene: IL6ST was added
gene: IL6ST was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: IL6ST was set to BIALLELIC, autosomal or pseudoautosomal
Added comment: • A homozygous non-synonymous variant in IL6ST (p.(Arg281Gln)) was described in a patient with craniosynostosis and retained deciduous teeth. Findings were supported using a mouse model with the missense variant which resulted in lower litter sizes, facial synostosis, and teeth abnormalities. The model phenocopies aspects of IL11RA deficiency in humans and mice (Schwerd et al., 2020).
• A patient with a homozygous variant in IL6ST presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. They were shown to harbour a p.(Asn404Tyr) missense substitution (Schwerd et al., 2017).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 FBXO11 Rebecca Tooze gene: FBXO11 was added
gene: FBXO11 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: FBXO11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: FBXO11 was set to GREEN
Added comment: • A de novo insertion was identified within the 100kGP cohort of patients with craniosynostosis: c.2731_2732insGACA; p.(Thr911Argfs*5) (Hyder et al., 2021).
• Two patients were described with craniosynostosis and variants in FBXO11: c.2518T>C, p.(Ser840Pro) in an individual with sagittal synostosis, and hg19: chr2: g.48060020C>G, c.1042- 1G>C; p.(?) (Gregor et al., 2018).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 DPH1 Rebecca Tooze gene: DPH1 was added
gene: DPH1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: DPH1 was set to AMBER
Added comment: • A patient was described with short stature, sagittal craniosynostosis and dysmorphic features including scaphocephaly, sparse hair, multiple dental anomalies, epicanthal folds and hypoplastic toenails to harbour a homozygous missense variant in DPH1: c.17T>A; p.(Met6Lys) (born to consanguineous parents).
• A family with two affected siblings were described and one was confirmed to have metopic synostosis. They harboured a recessive c.335A>G; p.(Tyr112Cys) variant (Urreizti et al., 2020).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 DPF2 Rebecca Tooze gene: DPF2 was added
gene: DPF2 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: DPF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: DPF2 was set to AMBER
Added comment: • Variants in DPF2 are associated with Coffin Siris syndrome. Two patients with sagittal synostosis were found to harbour a de novo c.1037A>G; p.(Asp346Gly) variant. A third patient with suspected metopic synostosis, owing to trigonocephaly, was identified with a c.1099+1G>A; p.(Asp340Glufs*12) frameshifting variant. All patients displayed phenotypic features of Coffin Siris syndrome (Vasileiou et al., 2018).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 CDK13 Rebecca Tooze gene: CDK13 was added
gene: CDK13 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: CDK13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: CDK13 was set to GREEN
Added comment: • A de novo missense variant was identified within the UK 100kGP cohort of patients with craniosynostosis: c.2563G>C; p.(Asp855His) (Hyder et al., 2021).
• A further de novo variant was identified in an individual within the Norwegian cohort: c.2524A>G; p.(Asn842Asp) (Tønne et al., 2021).
• Two patients were described with craniosynostosis in a cohort of patients with congenital heart defects, dysmorphic facial features, and intellectual disability (Bostwick et al., 2017)

Four independent cases identified.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 BCL11B Rebecca Tooze reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 ASXL3 Rebecca Tooze gene: ASXL3 was added
gene: ASXL3 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: ASXL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: ASXL3 was set to AMBER
Added comment: • A de novo c.3033dup; p.(Leu1012Serfs*23) was identified in a patient with metopic synostosis within the Norwegian cohort (Tønne et al., 2021).
• A six-year-old with microcephaly, autism, global developmental delay, and metopic craniosynostosis was found on exome sequencing to harbour a heterozygous two base pair de novo deletion, c.1897_1898delCA; p.(Gln633Valfs*13) in ASXL3 (Dinwiddie et al., 2013).
• A heterozygous de novo single nucleotide variant (c.3039+1G>A; p.(?)) in the invariant “GT” splice donor site of exon 11 was identified in an individual with a prominent forehead, thick eyebrows, long lashes, exotropia, depressed nasal ridge, thin upper lip vermillion, hirsutism, microcephaly, bilateral camptodactyly of third, fourth and fifth fingers, deep palmar creases, and small hands and feet. Craniosynostosis is not confirmed (Hori et al., 2016).

Two cases of loss-of-function variants in ASXL3; only one has radiologically confirmed craniosynostosis.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 ARID1B Rebecca Tooze gene: ARID1B was added
gene: ARID1B was added to Craniosynostosis. Sources: Literature,Research
Mode of inheritance for gene: ARID1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: ARID1B was set to GREEN
Added comment: • Analysis of the UK 100kGP identified a frameshift variant in ARID1B in a patient with intellectual disability and sagittal synostosis: c.3594delinsCCCCCA; p.(Gly1199Profs*14) (Hyder et al., 2021).
• A further frameshifting variant was described in an individual within the Chinese cohort with sagittal craniosynostosis c.2346_2352del; p.(Ser784Cysfs*59) (Chen et al., 2022).
• An additional patient was described with trigonocephaly and motor developmental delay with a variant in ARID1B: c.2277delC; p.(Pro760fs) (Suzuki et al., 2020).
• A de novo variant affecting ARID1B (c.1468_1472delTGGGC; p.(Trp490Glyfs*43)) was identified in an individual with craniosynostosis out of a cohort of neurodevelopmental disorder patients (Mignot et al., 2016).
Sources: Literature, Research
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 SH3PXD2B Rebecca Tooze changed review comment from: • Two heterozygous variants were identified in the Clarke cohort: c.1265T>C; p.(Ile433Thr) and c.2276C>G; p.(Pro759Arg) (Clarke et al., 2018) - see review: doi.org/10.3390/genes14030615; to: • Two heterozygous variants were identified in the Clarke cohort: c.1265T>C; p.(Ile433Thr) and c.2276C>G; p.(Pro759Arg) (Clarke et al., 2018). Other documented cases are homozygous so likely incidental. - see review: doi.org/10.3390/genes14030615
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 SH3PXD2B Rebecca Tooze reviewed gene: SH3PXD2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 RSPRY1 Rebecca Tooze reviewed gene: RSPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 NFIX Rebecca Tooze reviewed gene: NFIX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 KAT6B Rebecca Tooze reviewed gene: KAT6B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 IRX5 Rebecca Tooze reviewed gene: IRX5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 IFT43 Rebecca Tooze reviewed gene: IFT43: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 IFT140 Rebecca Tooze reviewed gene: IFT140: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 GPC3 Rebecca Tooze reviewed gene: GPC3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 FREM1 Rebecca Tooze reviewed gene: FREM1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 FGF9 Rebecca Tooze reviewed gene: FGF9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 FBN1 Rebecca Tooze reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 AXIN2 Rebecca Tooze reviewed gene: AXIN2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 AHDC1 Rebecca Tooze reviewed gene: AHDC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 ADAMTSL4 Rebecca Tooze reviewed gene: ADAMTSL4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 ADAMTSL4 Rebecca Tooze Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 ADAMTSL4 Rebecca Tooze reviewed gene: ADAMTSL4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 SOX6 Rebecca Tooze reviewed gene: SOX6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 SMAD3 Rebecca Tooze reviewed gene: SMAD3: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.3390/genes14030615; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 PRRX1 Rebecca Tooze reviewed gene: PRRX1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.3390/genes14030615; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 RNU12 Eleanor Williams Tag gene-checked tag was added to gene: RNU12.
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 ISCA-37420-Loss Arina Puzriakova Phenotypes for Region: ISCA-37420-Loss were changed from Koolen-de Vries/KANSL haploinsufficiency syndrome. to Koolen-De Vries syndrome, OMIM:610443; Developmental delay/intellectual disability, hypotonia, distinctive facial features, congenital malformations, and behavioural feature
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.3 NFIA Mafalda Gomes Tag Q2_22_rating was removed from gene: NFIA.
Tag Q2_22_NHS_review was removed from gene: NFIA.
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.3 NFIA Achchuthan Shanmugasundram reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.2 NFIA Mafalda Gomes Source Expert Review Green was added to NFIA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 BCL11B Helen Lord changed review comment from: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

310673176 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list; to: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

31067316 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 BCL11B Helen Lord gene: BCL11B was added
gene: BCL11B was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: BCL11B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BCL11B were set to 36275064; 310673176; 34900871; 36512050; 36470856
Phenotypes for gene: BCL11B were set to Craniosynostosis and global developmental delay
Review for gene: BCL11B was set to GREEN
Added comment: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan.
Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited.
The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins.

310673176 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis.
Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes.
Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7.
introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures.

34900871 Gaillard et al, 2021, 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6.

36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient.

36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs).

Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken.

4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Rare syndromic craniosynostosis or isolated multisuture synostosis v3.0 Catherine Snow promoted panel to version 3.0
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.76 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Parenti-Mignot neurodevelopmental syndrome, OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.75 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.75 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.75 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from 185900; chr2q35dup syndrome 185900; Acrocapitofermoral dysplasia 607778; bracydactyly type A1 112500 to Syndactyly, type 1, with or without craniosynostosis, OMIM:185900; Chr2q35dup syndrome
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.74 NFIA Eleanor Williams Classified gene: NFIA as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.74 NFIA Eleanor Williams Gene: nfia has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Tag Q2_22_rating tag was added to gene: NFIA.
Tag Q2_22_NHS_review tag was added to gene: NFIA.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Classified gene: NFIA as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Added comment: Comment on list classification: As Expert reviewer notes, there are sufficient cases reported with a craniosynostosis phenotype and variants in this gene to promote it to green following GMS review.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.73 NFIA Eleanor Williams Gene: nfia has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.72 NFIA Eleanor Williams Phenotypes for gene: NFIA were changed from to Metopic synostosis, hydrocephalus, thin corpus callosum, mild developmental delay, autism, macrocephaly
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.71 NFIA Eleanor Williams Mode of inheritance for gene: NFIA was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.70 NFIA Eleanor Williams Publications for gene: NFIA were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.69 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Resistance to insulin-like growth factor I to Insulin-like growth factor I, resistance to, OMIM:270450
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.68 SIX1 Arina Puzriakova Publications for gene: SIX1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37441-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37441-Loss was changed from 80 to 60.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 B3GAT3 Eleanor Williams Tag Q3_21_rating was removed from gene: B3GAT3.
Tag Q3_21_NHS_review was removed from gene: B3GAT3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 RNU12 Eleanor Williams Tag Q3_21_rating was removed from gene: RNU12.
Tag Q3_21_expert_review was removed from gene: RNU12.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 MASP1 Eleanor Williams Tag Q3_21_rating was removed from gene: MASP1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 ZNF462 Eleanor Williams Tag Q3_21_rating was removed from gene: ZNF462.
Tag Q1_22_NHS_review was removed from gene: ZNF462.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 LTBP1 Eleanor Williams Tag Q3_21_rating was removed from gene: LTBP1.
Tag Q1_22_NHS_review was removed from gene: LTBP1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 HNRNPK Eleanor Williams Tag Q3_21_rating was removed from gene: HNRNPK.
Tag Q1_22_NHS_review was removed from gene: HNRNPK.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 CHD7 Eleanor Williams Tag Q3_21_rating was removed from gene: CHD7.
Tag Q3_21_NHS_review was removed from gene: CHD7.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 ACTG1 Eleanor Williams Tag Q3_21_rating was removed from gene: ACTG1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 ACTB Eleanor Williams Tag Q3_21_rating was removed from gene: ACTB.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 ZNF462 Eleanor Williams commented on gene: ZNF462: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 RNU12 Eleanor Williams commented on gene: RNU12: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. It has been agreed that this gene should remain amber at this time.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 MASP1 Eleanor Williams commented on gene: MASP1: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. It has been agreed that this gene should remain amber at this time.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 LTBP1 Eleanor Williams commented on gene: LTBP1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 HNRNPK Eleanor Williams commented on gene: HNRNPK: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 CHD7 Eleanor Williams commented on gene: CHD7: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 ACTG1 Eleanor Williams commented on gene: ACTG1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.65 ACTB Eleanor Williams commented on gene: ACTB: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.64 ZNF462 Eleanor Williams Source Expert Review Green was added to ZNF462.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.64 LTBP1 Eleanor Williams Source Expert Review Green was added to LTBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.64 HNRNPK Eleanor Williams Source Expert Review Green was added to HNRNPK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.64 CHD7 Eleanor Williams Source Expert Review Green was added to CHD7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.64 ACTG1 Eleanor Williams Source Expert Review Green was added to ACTG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.64 ACTB Eleanor Williams Source Expert Review Green was added to ACTB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 B3GAT3 Eleanor Williams Tag for-review was removed from gene: B3GAT3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 SOX6 Eleanor Williams Tag for-review was removed from gene: SOX6.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 PTCH1 Eleanor Williams Tag for-review was removed from gene: PTCH1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 SIX1 Eleanor Williams Tag for-review was removed from gene: SIX1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 TRAF7 Eleanor Williams Tag for-review was removed from gene: TRAF7.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 SOX6 Eleanor Williams commented on gene: SOX6: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed. No new evidence. For-review tag should have been removed after Helen Lord review in Jan 2021.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 PTCH1 Eleanor Williams commented on gene: PTCH1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 SIX1 Eleanor Williams commented on gene: SIX1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 B3GAT3 Eleanor Williams commented on gene: B3GAT3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.63 TRAF7 Eleanor Williams commented on gene: TRAF7: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.62 PTCH1 Eleanor Williams Source Expert Review Green was added to PTCH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.62 SIX1 Eleanor Williams Source Expert Review Green was added to SIX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.62 B3GAT3 Eleanor Williams Source Expert Review Green was added to B3GAT3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.62 TRAF7 Eleanor Williams Source Expert Review Green was added to TRAF7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 NFIA Helen Lord reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35080095, 31754721, 33288889; Phenotypes: Metopic synostosis, hydrocephalus, thin corpus callosum, mild developmental delay, autism, macrocephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 ZNF462 Eleanor Williams commented on gene: ZNF462: Helen Lord review concurs with proposed green rating.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 ZNF462 Eleanor Williams Tag Q1_22_NHS_review tag was added to gene: ZNF462.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 HNRNPK Eleanor Williams Tag Q1_22_NHS_review tag was added to gene: HNRNPK.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 LTBP1 Eleanor Williams commented on gene: LTBP1: Helen Lord's review concurs with the recommendation to rate this gene green.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 LTBP1 Eleanor Williams Tag Q1_22_NHS_review tag was added to gene: LTBP1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 HNRNPK Eleanor Williams commented on gene: HNRNPK: Review and publication noted by Helen Lord adds further weight to rating this gene green.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 HNRNPK Eleanor Williams Added comment: Comment on publications: Added further paper PMID:32588992 - Yamada et al 2020
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.61 HNRNPK Eleanor Williams Publications for gene: HNRNPK were set to 26173930; 26954065; 28771707; 29904177; 24501764; 25348648; 28374925
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 HNRNPK Helen Lord reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588992; Phenotypes: Au Kline syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 LTBP1 Helen Lord reviewed gene: LTBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33991472; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 MASP1 Helen Lord reviewed gene: MASP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21258343, 7677137, 29168297; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 MASP1 Helen Lord Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 MASP1 Helen Lord commented on gene: MASP1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 ZNF462 Helen Lord reviewed gene: ZNF462: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513610, 31361404; Phenotypes: Weiss Kruszka syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 CHD7 Helen Lord changed review comment from: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review; to: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 CHD7 Helen Lord changed review comment from: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review; to: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 B3GAT3 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: B3GAT3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 HNRNPK Ivone Leong Tag Q3_21_rating tag was added to gene: HNRNPK.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 AXIN2 Arina Puzriakova Mode of inheritance for gene: AXIN2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.59 AXIN2 Arina Puzriakova Phenotypes for gene: AXIN2 were changed from Oligodontia-colorectal cancer syndrome 604025 to Oligodontia-colorectal cancer syndrome, OMIM:608615
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Classified gene: SMAD3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Added comment: Comment on list classification: On advice from Genomics England clinical team, promoting this gene from grey to amber. The number of cases with a craniosynostosis phenotype is borderline so rating as amber for now. Only 1 biallelic case reported so far so keeping the mode of inheritance as monoallelic.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Gene: smad3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.57 SMAD3 Eleanor Williams Phenotypes for gene: SMAD3 were changed from Loeys-Dietz syndrome 3, MIM# 613795 to Loeys-Dietz syndrome 3, OMIM:613795
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.56 SMAD3 Eleanor Williams Publications for gene: SMAD3 were set to 20301312; 29392890
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.55 IFT122 Sarah Leigh Publications for gene: IFT122 were set to 24689072; 20493458
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.54 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from cranioectodermal dysplasia; Cranioectodermal dysplasia type 1 218330 to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.53 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 147920; 147920 to Kabuki syndrome 1, OMIM:147920
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.52 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome to Alagille syndrome 1, OMIM:118450
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.51 GINS2 Arina Puzriakova gene: GINS2 was added
gene: GINS2 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS2 were set to 34353863
Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome with craniosynostosis
Review for gene: GINS2 was set to RED
Added comment: Sa et al., 2021 (PMID: 34353863) identified a patient presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. A homozygous missense variant (c.341G>T, p.Arg114Leu) in GINS2 was identified that was heterozygous in both unaffected parents. Some supportive functional data included.

GINS2 is not currently not associated with any phenotype in OMIM or G2P and no additional cases have been identified to date. Rating Red, awaiting further evidence.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.50 RNU12 Eleanor Williams Classified gene: RNU12 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.50 RNU12 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. It could be promoted to green after GMS review as there are 3 unrelated cases with a craniosynostosis phenotype. However, variants in this gene would not currently be reported as it is not a protein coding gene. An Ensembl ID also needs to be added before it is promoted to green.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.50 RNU12 Eleanor Williams Gene: rnu12 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.49 RNU12 Eleanor Williams Tag Q3_21_rating tag was added to gene: RNU12.
Tag Q3_21_expert_review tag was added to gene: RNU12.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.49 RNU12 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: RNU12.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.49 RNU12 Eleanor Williams Phenotypes for gene: RNU12 were changed from CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations to CDAGS syndrome, OMIM:603116; craniosynostosis-anal anomalies-porokeratosis syndrome, MONDO:001128
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 RNU12 Eleanor Williams edited their review of gene: RNU12: Changed phenotypes to: CDAGS syndrome, OMIM:603116, craniosynostosis-anal anomalies-porokeratosis syndrome, MONDO:0011287
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 RNU12 Eleanor Williams reviewed gene: RNU12: Rating: ; Mode of pathogenicity: None; Publications: 34085356; Phenotypes: CDAGS syndrome, OMIM:603116; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 LTBP1 Eleanor Williams Tag Q3_21_rating tag was added to gene: LTBP1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 LTBP1 Eleanor Williams Classified gene: LTBP1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 LTBP1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 4 cases reported with craniosynostosis in 6/8 individuals
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 LTBP1 Eleanor Williams Gene: ltbp1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.47 LTBP1 Eleanor Williams Phenotypes for gene: LTBP1 were changed from Craniosynostosis; cutis laxa; intelectual disability to Cutis laxa, autosomal recessive, type IIE, OMIM:619451; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.46 LTBP1 Eleanor Williams edited their review of gene: LTBP1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.46 LTBP1 Eleanor Williams reviewed gene: LTBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33991472; Phenotypes: Cutis laxa, autosomal recessive, type IIE, OMIM:619451, craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.46 CHD7 Eleanor Williams Classified gene: CHD7 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.46 CHD7 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommedation of green rating following GMS review. 3 cases reported with a craniosynostosis phenotype and supported model organism data, although incomplete penetrance is noted.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.46 CHD7 Eleanor Williams Gene: chd7 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.45 CHD7 Eleanor Williams Phenotypes for gene: CHD7 were changed from craniosynostosis to CHARGE syndrome, OMIM:214800; CHARGE syndrome, MONDO:0008965
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.44 CHD7 Eleanor Williams Publications for gene: CHD7 were set to 33844462; 30498854; 33288889
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.43 CHD7 Eleanor Williams Tag Q3_21_rating tag was added to gene: CHD7.
Tag Q3_21_NHS_review tag was added to gene: CHD7.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.43 CHD7 Eleanor Williams reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33844462, 30498854, 33288889, 24975120, 22363697; Phenotypes: CHARGE syndrome, OMIM:214800, CHARGE syndrome, MONDO:0008965; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.43 ZNF462 Eleanor Williams Classified gene: ZNF462 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.43 ZNF462 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. Metopic ridging or craniosynostosis reported in 6 cases with a plausible disease causing variant in ZNF462.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.43 ZNF462 Eleanor Williams Gene: znf462 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.42 ZNF462 Eleanor Williams Phenotypes for gene: ZNF462 were changed from Weiss-Kruszka syndrome, MIM# 618619 to Weiss-Kruszka syndrome, OMIM:618619; weiss-kruszka syndrome, MONDO:0032836
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.41 ZNF462 Eleanor Williams Publications for gene: ZNF462 were set to 28513610
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 ZNF462 Eleanor Williams Tag Q3_21_rating tag was added to gene: ZNF462.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 ZNF462 Eleanor Williams reviewed gene: ZNF462: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513610, 31361404; Phenotypes: Weiss-Kruszka syndrome, OMIM:618619, weiss-kruszka syndrome, MONDO:0032836; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 SMAD3 Eleanor Williams changed review comment from: Associated with Loeys-Dietz syndrome 3 #613795 (AD) in OMIM but craniosynostosis not listed as a clinical feature.

PMID: 20301312 - Loeys and Dietz (2008 updated 2018) - Gene Reviews - states that in severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis.

PMID: 29392890 - Schepers et al 2018 - review of genes/variants associated with Loeys-Dietz syndrome. Table 5 indicates that only SMAD3 variants are associated with craniosynostosis and text says that "craniosynostosis has only been reported once in a SMAD3 patient" but no reference is given.

Looking at reported phenotypes for LDS patients with a SMAD3 variant:
PMID: 31569402 - Camerota et al 2019 - report 4 families with LDS and SMAD3 variants. 3/9 individuals from 3 different Italian families presented with dolichocephaly among other phenotypes. 4 families reported with SMAD3 variants in total, each with a different likely causative variant.

PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. Dolichocephaly in the proband is mentioned.; to: Associated with Loeys-Dietz syndrome 3 #613795 (AD) in OMIM but craniosynostosis not listed as a clinical feature.

PMID: 20301312 - Loeys and Dietz (2008 updated 2018) - Gene Reviews - states that in severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis.

PMID: 29392890 - Schepers et al 2018 - review of genes/variants associated with Loeys-Dietz syndrome. Table 5 indicates that only SMAD3 variants are associated with craniosynostosis and text says that "craniosynostosis has only been reported once in a SMAD3 patient" but no reference is given.

Looking at reported phenotypes for LDS patients with a SMAD3 variant and craniosynostosis phenotype:
PMID: 31569402 - Camerota et al 2019 - report 4 families with LDS and SMAD3 variants. 3/9 individuals from 3 different Italian families presented with dolichocephaly among other phenotypes. 4 families reported with SMAD3 variants in total, each with a different likely causative variant.

PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. Dolichocephaly in the proband is mentioned.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 SMAD3 Eleanor Williams reviewed gene: SMAD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29392890, 31569402, 32935439; Phenotypes: Loeys-Dietz syndrome 3 OMIM:613795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 ACTG2 Zornitza Stark Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 MASP1 Eleanor Williams Classified gene: MASP1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 MASP1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a green recommendation for GMS review. Publications from Basdemirci et al and Atik et al suggest further cases where craniosynostosis is a feature.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 MASP1 Eleanor Williams Gene: masp1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.39 MASP1 Eleanor Williams Phenotypes for gene: MASP1 were changed from 3MC syndrome 1 257920 to 3MC syndrome 1, OMIM:257920; 3MC syndrome 1, MONDO:0009770
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.38 MASP1 Eleanor Williams Publications for gene: MASP1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.37 MASP1 Eleanor Williams Mode of inheritance for gene: MASP1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 MASP1 Eleanor Williams Tag Q2_21_rating was removed from gene: MASP1.
Tag Q3_21_rating tag was added to gene: MASP1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 MASP1 Eleanor Williams Tag Q2_21_rating tag was added to gene: MASP1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 MASP1 Eleanor Williams edited their review of gene: MASP1: Added comment: Checking for further reported cases:

PMID: 30601195 - Basdemirci et al 2019 - 3 siblings with 3MC syndrome in which a novel homozygous missense mutation, p.V704G, in MASP1 was identified in 2 of the siblings (not clear if the 3rd sibling was analysed). Craniosynostosis/skull asymmetry is reported in 2 siblings but no details given.

PMID: 29407414 - Graul-Neumann et al 2018 - 1adult female with a homozygous 2kb deletion, partially affecting exon 12 of MASP1 found by trio exome sequencing. She has the characteristic facial gestalt and typical multiple congenital anomalies but lacking the key feature cleft lip and palate. At birth craniofacial dysmorphism with skull asymmetry, open sutura metopica and facial asymmetry were noted among other features.

PMID: 26419238 - Atik et al 2015 - report on 6 unrelated children with 3MC1 syndrome. Sanger sequencing of MASP1 found 2 different splice site variants, and 3 different missense variants in the 6 probands. Two are reported to have craniosynostosis/skull asymmetry but no details given.

No mention of craniosynostosis or skull asymmetry:

PMID: 21035106 - Sirmaci et al 2010 - 3 individuals from 2 consanguineous Turkish families with 3MC. A missense and nonsense mutation in MASP1 were found by WES and Sanger sequencing in the two families respectively. Craniosynostosis is NOT mentioned as part of the phenotype.; Changed publications to: 30601195, 29407414, 26419238, 21035106, 21258343, 26789649
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 HNRNPK Eleanor Williams Classified gene: HNRNPK as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 HNRNPK Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, with a recommendation for green rating following GMS review. 4 cases reported with craniosynostosis and variants in this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 HNRNPK Eleanor Williams Gene: hnrnpk has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.35 HNRNPK Eleanor Williams Phenotypes for gene: HNRNPK were changed from Au-Kline syndrome, MIM# 616580 to Au-Kline syndrome, OMIM:616580
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.34 HNRNPK Eleanor Williams Publications for gene: HNRNPK were set to 26173930; 26954065; 29904177
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.33 HNRNPK Eleanor Williams reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: 26173930, 26954065, 28771707, 29904177, 24501764, 25348648, 28374925; Phenotypes: Au-Kline syndrome, OMIM:616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.33 FGF10 Eleanor Williams Classified gene: FGF10 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.33 FGF10 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.33 FGF10 Eleanor Williams Gene: fgf10 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.32 FGF10 Eleanor Williams Phenotypes for gene: FGF10 were changed from Craniosynostosis to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 FGF10 Eleanor Williams changed review comment from: As expert reviewer reports PMID: 29215649 (Lee et al 2018) conducted a study in which 233 individuals with craniosynostosis where screened with a 20-gene panel which was designed based on the genes' association with craniosynostosis. Heterozygous variants (1 frameshift, 1 nonsense) were identified in 2 patients.; to: As expert reviewer reports PMID: 29215649 (Lee et al 2018) conducted a study in which 233 individuals with craniosynostosis where screened with a 20-gene panel which was designed based on the genes' association with craniosynostosis. Heterozygous variants (1 frameshift, 1 nonsense) in FGF10 were identified in 2 patients.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 FGF10 Eleanor Williams reviewed gene: FGF10: Rating: AMBER; Mode of pathogenicity: None; Publications: 29215649; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 B3GAT3 Eleanor Williams Tag Q3_21_rating tag was added to gene: B3GAT3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 ACTG2 Eleanor Williams Classified gene: ACTG2 as No list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 ACTG2 Eleanor Williams Added comment: Comment on list classification: Keeping this gene grey as it is not the correct gene for the panel (should be ACTG1).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 ACTG2 Eleanor Williams Gene: actg2 has been removed from the panel.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.30 ACTG2 Eleanor Williams commented on gene: ACTG2
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.30 ACTG1 Eleanor Williams Classified gene: ACTG1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.30 ACTG1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, with the recommendation of green rating following GMS review. More than 3 cases reported with disease-associated variants in this gene, with Trigonocephaly/metopic ridge reported as part of the phenotype.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.30 ACTG1 Eleanor Williams Gene: actg1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.29 ACTG1 Eleanor Williams Tag Q3_21_rating tag was added to gene: ACTG1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.29 ACTG1 Eleanor Williams gene: ACTG1 was added
gene: ACTG1 was added to Craniosynostosis. Sources: Literature
missense tags were added to gene: ACTG1.
Mode of inheritance for gene: ACTG1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACTG1 were set to 22366783; 25052316; 27240540
Phenotypes for gene: ACTG1 were set to Baraitser-Winter syndrome 2, OMIM:614583
Review for gene: ACTG1 was set to GREEN
Added comment: Associated with Baraitser-Winter syndrome 2 OMIM:614583 (AD) in OMIM.

PMID: 22366783 - Rivière et al 2012 - 8 patients with Baraitser-Winter syndrome in which a heterozygous missense mutation was identified in the ACTG1 gene. In 7 patients the mutation was found to have occurred de novo (no parental DNA in 8th patient). Trigonocephaly was noted in 7 of the patients.

PMID: 25052316 - Verloes et al 2015 - report on 1 new case of a patient with a missense variant in ACTG1 (same variant as reported in Riviere et al) and bring together information from the Riviere patients with this one. They state that Trigonocephaly/metopic ridge is reported in 4/8 cases (50%) which contradicts the table in the Riviere paper which puts the number as higher.

PMID: 27240540 - Donato et al 2016 - report on 7 new unrelated patients with 6 mutations in ACTG1. Clinical photographs were available for 6 of these patients, and only 1/6 displayed a metopic ridge.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.28 ACTB Eleanor Williams Classified gene: ACTB as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.28 ACTB Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. There are more than 3 cases with plausible disease causing variants in this gene, and a relevant phenotype.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.28 ACTB Eleanor Williams Gene: actb has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.27 ACTB Eleanor Williams Phenotypes for gene: ACTB were changed from Baraitser-Winter syndrome 1, MIM# 243310 to Baraitser-Winter syndrome 1, OMIM:243310; Baraitser-Winter syndrome 1, MONDO:0009470
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.26 ACTB Eleanor Williams Publications for gene: ACTB were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 ACTB Eleanor Williams Tag missense tag was added to gene: ACTB.
Tag Q3_21_rating tag was added to gene: ACTB.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 ACTB Eleanor Williams reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 22366783, 23649928, 23756437; Phenotypes: Baraitser-Winter syndrome 1, OMIM:243310, Baraitser-Winter syndrome 1, MONDO:0009470; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 CHD5 Ivone Leong Tag watchlist tag was added to gene: CHD5.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 CHD5 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

As less than half the cases had craniosynostosis, this gene has been given an Amber rating awaiting more cases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 CHD5 Ivone Leong Entity copied from Intellectual disability v3.1197
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 CHD5 Ivone Leong gene: CHD5 was added
gene: CHD5 was added to Craniosynostosis. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.24 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from frontometaphyseal dysplasia; oto-palato-digital syndromes; melnick-needles syndrome to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 RNU12 Zornitza Stark gene: RNU12 was added
gene: RNU12 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356
Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations
Review for gene: RNU12 was set to GREEN
Added comment: 5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events. Craniosynostosis is a major feature of the condition.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 LTBP1 Zornitza Stark gene: LTBP1 was added
gene: LTBP1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to Craniosynostosis; cutis laxa; intelectual disability
Review for gene: LTBP1 was set to GREEN
Added comment: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 CHD7 Helen Lord gene: CHD7 was added
gene: CHD7 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: CHD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD7 were set to 33844462; 30498854; 33288889
Phenotypes for gene: CHD7 were set to craniosynostosis
Review for gene: CHD7 was set to AMBER
Added comment: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 KANSL1-AS1 Arina Puzriakova Tag curated_removed tag was added to gene: KANSL1-AS1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 PJA1 Eleanor Williams commented on gene: PJA1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 PJA1 Eleanor Williams Phenotypes for gene: PJA1 were changed from Trigonocephaly; Intellectual disability to Trigonocephaly; Intellectual disability; Neurodevelopmental disorders
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 PTCH1 Eleanor Williams commented on gene: PTCH1: This gene should be discussed as to gene rating/phenotypic scope of this panel at the next GMS review.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 SOX6 Eleanor Williams changed review comment from: 3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber.; to: 3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients.. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber but based on review by Expert Reviewer Helen Lord, will keep amber for now.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 SOX6 Eleanor Williams commented on gene: SOX6: 3 unrelated cases reported in Tolchin et al, 2020 with a craniosynotosis phenotype but segregation data only for 2 patients. Additional evidence in Tagariello et al 2004 who reports a patient with brachycephaly and a translocation disrupting SOX6. Borderline green/amber.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 SOX6 Eleanor Williams changed review comment from: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.; to: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the third this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 TRAF7 Eleanor Williams edited their review of gene: TRAF7: Added comment: Both Andrew Wilkie and Helen Lord cite a publication that lists several patients with craniosynostosis and TRAF7 variants. Therefore this gene has a green rating recommendation for the next review.; Changed rating: GREEN
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.22 B3GAT3 Eleanor Williams Phenotypes for gene: B3GAT3 were changed from Craniosynostosis and bone fragility to Craniosynostosis and bone fragility; Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects OMIM:245600; Larsen-like syndrome, B3GAT3 type MONDO:0009511
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.21 B3GAT3 Eleanor Williams Publications for gene: B3GAT3 were set to 28771243
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.20 B3GAT3 Eleanor Williams Classified gene: B3GAT3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.20 B3GAT3 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber for now, but with recommendation for green rating following GMS review. 3 independent cases with dolichocephaly/craniosynostosis reported and variants in B3GAT3. Cases from Morocco and India have a c.667G>A (p.Gly223Ser) variant but Ritelli et al 2019 reports an additional case with two different compound het variants.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.20 B3GAT3 Eleanor Williams Gene: b3gat3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 B3GAT3 Eleanor Williams Tag for-review tag was added to gene: B3GAT3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 B3GAT3 Eleanor Williams commented on gene: B3GAT3: As reported by 2 expert reviewers, PMID:31438591 (Ritelli et al 2019) report a further case of a patient with compound het missense changes (c.481C>T, p.(Arg161Trp) and c.889C>T (p.(Arg297Trp)) in B3GAT3 and a clinical presentation suggestive of spondylodysplastic Ehlers-Danlos syndrome which includes dolichocephaly. In Table 2 the paper lists the clinical features of all patients with B3GAT3 variants reported to date, however, some of these patients appear to have variants in AEBP1 (ENSG00000106624) rather than B3GAT3 (ENSG00000149541) e.g. PMID: 29606302 (reference 2 in the table).

PMID: 31196143 - Colman et al 2019 - report an Indian boy with complex linkeropathy and phenotypic features that include dolichocephaly. He was found to have a homozygous variant in B3GAT3 (c.667G > A, p.(Gly223Ser)) that was previously reported by Yauy et al. Another patient with a B3GAT3 variant is reported but dolichocephaly is not noted.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 B3GAT3 Helen Lord reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31438591; Phenotypes: craniosynostosis MIM245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Helen Lord reviewed gene: TRAF7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32376980, 29961569; Phenotypes: craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 SOX6 Helen Lord reviewed gene: SOX6: Rating: AMBER; Mode of pathogenicity: None; Publications: 32442410; Phenotypes: Developmental delay, intellectual disability, craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PTCH1 Helen Lord reviewed gene: PTCH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: metopic synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Neurodevelopmental disorders, trigonocephaly; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord commented on gene: PJA1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 PJA1 Helen Lord reviewed gene: PJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32530565; Phenotypes: Neurodevelopmental disorders, trigonocephaly; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Tag for-review tag was added to gene: TRAF7.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Classified gene: TRAF7 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with recommendation for green rating following GMS review. Expert reviewer highlights more than 3 cases in which patients with variants in TRAF7 have a craniosynostosis phenotype.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.19 TRAF7 Eleanor Williams Gene: traf7 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Tag for-review tag was added to gene: PTCH1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Classified gene: PTCH1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for green review following evidence provided by expert reviewer.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.18 PTCH1 Eleanor Williams Gene: ptch1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.17 SIX1 Eleanor Williams Classified gene: SIX1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.17 SIX1 Eleanor Williams Added comment: Comment on list classification: Leaving the rating at amber for now, but with recommendation for green rating following the next GMS review. More than 3 cases with a craniosynostosis phenotype and variants in this gene now published.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.17 SIX1 Eleanor Williams Gene: six1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 SIX1 Eleanor Williams Tag for-review tag was added to gene: SIX1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 TRAF7 Andrew Wilkie gene: TRAF7 was added
gene: TRAF7 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRAF7 were set to 32376980
Phenotypes for gene: TRAF7 were set to craniosynostosis
Penetrance for gene: TRAF7 were set to Incomplete
Review for gene: TRAF7 was set to GREEN
Added comment: Castilla-Vallmanya et al (2020) reported the phenotypes associated with 45 heterozygous variants in TRAF7, missense mutations of which cause a recently recognised neurodevelopmental disorder. 3 of these individuals were reported to have craniosynostosis.
The submitter is aware of two additional unpublished cases with TRAF7 missense variants and craniosynostosis; one of these was missed in 100kGP by the GEL/GMC pipeline because TRAF7 was not included in PanelApp, the other is an unpublished case from Rotterdam.
In summary there appears to be sufficient evidence that craniosynostosis is a significant albeit low-frequency complication of pathogenic TRAF7 variants, which cause a complex neurodevelopmental disorder.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 PTCH1 Andrew Wilkie gene: PTCH1 was added
gene: PTCH1 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTCH1 were set to 31578813
Phenotypes for gene: PTCH1 were set to metopic craniosynostosis
Penetrance for gene: PTCH1 were set to Incomplete
Review for gene: PTCH1 was set to GREEN
Added comment: Several lines of evidence support that heterozygous loss-of-function mutations in PTCH1, which cause the classical genetic disorder Gorlin (basal cell naevus) syndrome, rarely also cause metopic synostosis. It is especially important to recognise this association, given the implications for patient management from a diagnosis of Gorlin syndrome.
(1) Beltrami et al (see PMID 31578813) described a frameshift variant in PTCH1 in a child with metopic synostosis.
(2) At the ESHG conference 2020, Di Giovanni et al reported 2 cases of apparently isolated trigonocephaly found to have nonsense or frameshift varaints in PTCH1. The abstract is available on weblink: https://www.abstractsonline.com/pp8/#!/9102/presentation/1801.
(3) Deletions of 9q22.3 including PTCH1 are well recognised to be associated with metopic synostosis (reviewed Yamada PMID:32028043), although genes additional to PTCH1 are included in the deleted region.
(4) In the 100kGP, the submitter is aware of a case that was missed by GEL/GMC pipeline (found by research lab) because PTCH1 was not included in the Panel for craniosynostosis.
(5) The consequence of PTCH1 loss-of-function mutations is to increase hedgehog (Hh) signalling through de-repression of Smoothened. Mutations in other genes associated with Hh overactivity, in the genes SMO, RAB23 and MEGF8, are all associated with craniosynostosis and are green panel app genes. A mice mutated in the Ptch1 orthologue, dogface-like, has lambdoid craniosynostosis (PMID:23897749). Hence, a clear biological mechanism exists accounting for craniosynostosis.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 SIX1 Andrew Wilkie edited their review of gene: SIX1: Added comment: Calpena et al (2021) identified 7 families in which the proband had craniosynostosis (affecting at least the sagittal suture in all cases) and a heterozygous SIX1 variant (4 nonsense + 3 missense in highly conserved residues of SIX domain or homeodomain). SIX1 mutations (mostly missense) were previously described in branchio-otic syndrome (BOS). Patients and carriers in the extended family variably had features of BOS (including branchial cysts, ear tags or pits, and hearing loss), but there were also several non-penetrant heterozygous individuals, indicating substantial variation in expressivity.
The absolute proportion of all craniosynostosis cases found to have SIX1 variants was low (7/1629, 0.4%), but much higher [4/23 (17%)] in those with the rare "Mercedez-Benz" pattern (sagittal + bilambdoid synostosis).
SIX1 analysis is therefore particularly indicated in individuals with either (1) additional BOS features or (2) sagittal+bilambdoid synostosis.; Changed rating: GREEN; Changed publications: 33436522
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from AD MR type 57 - 618050 to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.15 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.15 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Classified gene: PJA1 as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on evidence provided in a single publication (PMID:32530565). Additional case supporting pathogenicity of other PJA1 variants required prior to inclusion on a diagnostic panel.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Gene: pja1 has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.13 PJA1 Arina Puzriakova gene: PJA1 was added
gene: PJA1 was added to Craniosynostosis. Sources: Expert list
founder-effect tags were added to gene: PJA1.
Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PJA1 were set to 32530565
Phenotypes for gene: PJA1 were set to Trigonocephaly; Intellectual disability
Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals from 5 independent families, of which 5 patients were diagnosed with mild trigonocephaly. Some supportive data in a mouse model. Individuals shared a common haplotype, suggestive of founder effect.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.12 ZIC1 Arina Puzriakova Phenotypes for gene: ZIC1 were changed from Craniosynostosis 6 616602; 616602 to ?Craniosynostosis 6, 616602; Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.11 ZIC1 Arina Puzriakova Added comment: Comment on publications: Added publications to support gene-disease association
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.11 ZIC1 Arina Puzriakova Publications for gene: ZIC1 were set to 26340333
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.10 SOX6 Arina Puzriakova Classified gene: SOX6 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.10 SOX6 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.10 SOX6 Arina Puzriakova Gene: sox6 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SOX6 Arina Puzriakova Tag for-review tag was added to gene: SOX6.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 ZNF462 Zornitza Stark gene: ZNF462 was added
gene: ZNF462 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF462 were set to 28513610
Phenotypes for gene: ZNF462 were set to Weiss-Kruszka syndrome, MIM# 618619
Review for gene: ZNF462 was set to GREEN
gene: ZNF462 was marked as current diagnostic
Added comment: Craniosynostosis observed in 38% of affected individuals.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SMAD3 Zornitza Stark gene: SMAD3 was added
gene: SMAD3 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: SMAD3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD3 were set to 20301312; 29392890
Phenotypes for gene: SMAD3 were set to Loeys-Dietz syndrome 3, MIM# 613795
Review for gene: SMAD3 was set to GREEN
Added comment: Craniosynostosis is a feature of LDS.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 MASP1 Zornitza Stark reviewed gene: MASP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7677137, 21258343; Phenotypes: 3MC syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 HNRNPK Zornitza Stark gene: HNRNPK was added
gene: HNRNPK was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: HNRNPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPK were set to 26173930; 26954065; 29904177
Phenotypes for gene: HNRNPK were set to Au-Kline syndrome, MIM# 616580
Review for gene: HNRNPK was set to GREEN
gene: HNRNPK was marked as current diagnostic
Added comment: Multiple unrelated individuals with Au-Kline syndrome (approx 1/3) have craniosynostosis - sagittal, metopic, lambdoid.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 FGF10 Zornitza Stark gene: FGF10 was added
gene: FGF10 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: FGF10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF10 were set to 29215649
Phenotypes for gene: FGF10 were set to Craniosynostosis
Review for gene: FGF10 was set to AMBER
Added comment: Two individuals reported with variants in this gene as part of a large craniosynostosis cohort.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 B3GAT3 Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31438591; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 ACTG2 Zornitza Stark gene: ACTG2 was added
gene: ACTG2 was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: ACTG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ACTG2 were set to Baraitser-Winter syndrome 2, MIM# 614583
Review for gene: ACTG2 was set to GREEN
Added comment: Metopic ridging is a key feature of this condition.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 ACTB Zornitza Stark gene: ACTB was added
gene: ACTB was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: ACTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ACTB were set to Baraitser-Winter syndrome 1, MIM# 243310
Review for gene: ACTB was set to GREEN
Added comment: Ridged metopic suture is a key feature of this condition.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SOX6 Eleanor Williams Phenotypes for gene: SOX6 were changed from craniosynostosis; intellectual disability to craniosynostosis
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.8 SOX6 Eleanor Williams Phenotypes for gene: SOX6 were changed from to craniosynostosis; intellectual disability
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.7 SOX6 Eleanor Williams Publications for gene: SOX6 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams changed review comment from: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.; to: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams Added comment: Comment on mode of inheritance: All patients reported by Tolchin et al were heterozygous
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams Mode of inheritance for gene: SOX6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Classified gene: SOX6 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Added comment: Comment on list classification: 4 patients reported with genomic alterations affecting SOX6 are now reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Gene: sox6 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.4 SOX6 Eleanor Williams commented on gene: SOX6: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.4 ISCA-37420-Loss Catherine Snow Mode of inheritance for Region: ISCA-37420-Loss was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.3 Eleanor Williams Panel version has been signed off
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 FBN1 Eleanor Williams commented on gene: FBN1: PMID: 16596670 - Ades et al 2006 - report 2 patients with heterozygous FBN1 mutations (Patients 1 and 2) and a patient with a heterozygous FBN1 deletion (Patient 5). Patient 1 had Marfan syndrome with scaphocephaly, unusually rounded orbital rims and recession of the right orbital and frontal regions. Coronal sutures were indistinct. The anterior half of the sagittal suture was fused. Patient 2 had severe early onset Marfan sydnrome and plagiocephaly with coronal, lambdoid, and sagittal sutures. Patient 5 had marfanoid (MD) features, mental retardation (MR), and dolichocephaly.

PMID: 27884935 - Miller et al 2017 - report a case of a patient with craniosynostosis and a de novo splice variant affecting FBN1. c.8226+5G>A.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 MASP1 Eleanor Williams changed review comment from: PMID: 21258343 - Rooryck et al 2011 - report 1 patient with a homozygous MASP1variant ( c.1489 C>T, p.His497Tyr) that segregated with 3MC syndrome in the family. The patient's features included craniosynostosis.

PMID: 26789649 - Urquhart et al 2016 - report 2 patients with homozygous variants in MASP1 (c.760A>T,p.(Leu 254*) and c.547G>T, p(.Val 183Leu) ) who have plagiocephaly and turricephaly respectively, but they note that craniosynostosis was not observed.; to: PMID: 21258343 - Rooryck et al 2011 - report 1 patient with a homozygous MASP1variant ( c.1489 C>T, p.His497Tyr) that segregated with 3MC syndrome in the family. The patient's features included craniosynostosis.

PMID: 26789649 - Urquhart et al 2016 - report two 3MC syndrome patients with homozygous variants in MASP1 (c.760A>T,p.(Leu 254*) and c.547G>T, p(.Val 183Leu) ) who have plagiocephaly and turricephaly respectively, but they note that craniosynostosis was not observed.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 MASP1 Eleanor Williams commented on gene: MASP1: PMID: 21258343 - Rooryck et al 2011 - report 1 patient with a homozygous MASP1variant ( c.1489 C>T, p.His497Tyr) that segregated with 3MC syndrome in the family. The patient's features included craniosynostosis.

PMID: 26789649 - Urquhart et al 2016 - report 2 patients with homozygous variants in MASP1 (c.760A>T,p.(Leu 254*) and c.547G>T, p(.Val 183Leu) ) who have plagiocephaly and turricephaly respectively, but they note that craniosynostosis was not observed.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 Eleanor Williams promoted panel to version 2.0
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.134 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.133 ISCA-37420-Loss Eleanor Williams commented on Region: ISCA-37420-Loss: GMS Musculoskeletal test group informed of amber rating at Webex. No objections.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.133 TFAP2B Eleanor Williams Classified gene: TFAP2B as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.133 TFAP2B Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green as 4 cases have been reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.133 TFAP2B Eleanor Williams Gene: tfap2b has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.132 TFAP2B Eleanor Williams Phenotypes for gene: TFAP2B were changed from to Char syndrome 169100
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.131 TFAP2B Eleanor Williams Publications for gene: TFAP2B were set to 31405973
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.130 TFAP2B Eleanor Williams commented on gene: TFAP2B: 4 cases reported
There are 4 cases reported in PMID: 31292255 (Correction in PMID: 31405973) 2 de novo and 2 inherited. There is evidence for reduced penetrance as in one case the variant was inherited from an unaffected parent.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.130 TFAP2B Eleanor Williams commented on gene: TFAP2B: Review from Helen Lord (Oxford University Hospitals NHS Trust):
Paper by Timberlake et al, 2019, PNAS, 116 (34) 17130 (PMID 31405973): 12 probands with syndromic craniosynostosis. Exome sequencing identified 4/12 TFAP2B variants – 3 of the patients had metopic synostosis and 1 had sagittal synostosis. 2 de novo (splicing and missense) and 2 rare transmitted LOF variants (nonsense variant (transmitted from an affected parent- looks like untreated metopic synostosis) and one affecting the initiating Met (transmitted from an unaffected parent)).

They comment that heterozygous damaging variants have been implicated in CHAR syndrome, and abnormal head shapes and ridging over the cranial sutures have been reported in several patients.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.130 TFAP2B Eleanor Williams gene: TFAP2B was added
gene: TFAP2B was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: TFAP2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TFAP2B were set to 31405973
Added comment: Gene suggested for inclusion by Helen Lord.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.129 ESCO2 Eleanor Williams Publications for gene: ESCO2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.128 ESCO2 Eleanor Williams Classified gene: ESCO2 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.128 ESCO2 Eleanor Williams Added comment: Comment on list classification: Changing the rating from red to amber. 2 published cases plus one seen in a clinic.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.128 ESCO2 Eleanor Williams Gene: esco2 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.127 ESCO2 Eleanor Williams edited their review of gene: ESCO2: Added comment: Review from Helen Lord:
PMID: 31192177 - Colombo et al 2019 - 2 unrelated children – one Turkish and one Iranian, both patients had craniosynostosis as part of their phenotype. WES on these two trios identified two different homozygous inactivating variants (one splicing and 1 frameshift) in the ESCO2 gene.

Personal communication from Professor Wilkie – seen a case personally (unpublished evidence)

Also
PMID: 19574259 - Vega et al 2010 - provide clinical data for 31 patients from 26 families with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Craniosynostosis is NOT mentioned directly in this paper.; Changed publications: 31192177
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.127 TMCO1 Eleanor Williams Phenotypes for gene: TMCO1 were changed from MR syndrome; Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism; skeletal anomalies to MR syndrome; Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism; skeletal anomalies; Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, 213980
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.126 TMCO1 Eleanor Williams changed review comment from: Associated with Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (#213980) in OMIM and Gene2Phenotype (confirmed)

PMID: 20018682 - Xin et al 2010 - identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. They identified a homozygous frameshift mutation, c.139_140delAG, in TMCO1 in all affected members of the extended pedigree. 2 of the 11 individuals showed craniosynostosis.

PMID: 24424126 - Pehlivan et al 2014 - report a patient with cerebro-facio-thoracic dysplasia with a homozygous splice-site mutation TMC01 identified using WES. Cranial MRI revealed frontotemporal atrophy, dilated lateral ventricles and a short, dysgenetic corpus callosum.

PMID: 24194475 - Alanay et al 2013 - identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in TMCO1 in 4 families of Turkish origin with Cerebrofaciothoracic dysplasia. Patient 4 from family 2 had a Prominent metopic suture (craniosynostosis).

3 cases with craniosynostosis reported.; to: Associated with Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (#213980) in OMIM and Gene2Phenotype (confirmed)

PMID: 20018682 - Xin et al 2010 - identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. They identified a homozygous frameshift mutation, c.139_140delAG, in TMCO1 in all affected members of the extended pedigree. 2 of the 11 individuals showed craniosynostosis.

PMID: 24424126 - Pehlivan et al 2014 - report a patient with cerebro-facio-thoracic dysplasia with a homozygous splice-site mutation TMC01 identified using WES. Cranial MRI revealed frontotemporal atrophy, dilated lateral ventricles and a short, dysgenetic corpus callosum.

PMID: 24194475 - Alanay et al 2013 - identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in TMCO1 in 4 families of Turkish origin with Cerebrofaciothoracic dysplasia. Patient 4 from family 2 had a Prominent metopic suture (craniosynostosis).

3 cases with craniosynostosis reported.

Other cases have been reported, but without craniosysnosotis e.g. PMID: 23320496, PMID: 31102500, PMID: 30556256
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.126 TMCO1 Eleanor Williams Publications for gene: TMCO1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.125 TMCO1 Eleanor Williams Classified gene: TMCO1 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.125 TMCO1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to green as there are 3 cases reported with craniosynostosis as a feature.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.125 TMCO1 Eleanor Williams Gene: tmco1 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124 TMCO1 Eleanor Williams commented on gene: TMCO1: Associated with Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (#213980) in OMIM and Gene2Phenotype (confirmed)

PMID: 20018682 - Xin et al 2010 - identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. They identified a homozygous frameshift mutation, c.139_140delAG, in TMCO1 in all affected members of the extended pedigree. 2 of the 11 individuals showed craniosynostosis.

PMID: 24424126 - Pehlivan et al 2014 - report a patient with cerebro-facio-thoracic dysplasia with a homozygous splice-site mutation TMC01 identified using WES. Cranial MRI revealed frontotemporal atrophy, dilated lateral ventricles and a short, dysgenetic corpus callosum.

PMID: 24194475 - Alanay et al 2013 - identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in TMCO1 in 4 families of Turkish origin with Cerebrofaciothoracic dysplasia. Patient 4 from family 2 had a Prominent metopic suture (craniosynostosis).

3 cases with craniosynostosis reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124 SEC24D Eleanor Williams commented on gene: SEC24D: After review with clinical experts from the GMS musculoskeletal specialist test group it was decided to keep this gene as amber based on the level of evidence for craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124 KMT2D Eleanor Williams commented on gene: KMT2D: Associated with Kabuki syndrome (#147920) in OMIM with many cases reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124 RUNX2 Eleanor Williams changed review comment from: Information about evidence for a CNV associated with Craniosynostosis has been submitted to ClinGen for curation (July 2019); to: Information about evidence for a CNV encompassing RUNX2 associated with Craniosynostosis has been submitted to ClinGen for curation (July 2019)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124 RUNX2 Eleanor Williams commented on gene: RUNX2: Information about evidence for a CNV associated with Craniosynostosis has been submitted to ClinGen for curation (July 2019)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124 Eleanor Williams List of related panels changed from Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis to Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; R100
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Control populations:
A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876)

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Control populations:
A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Control populations:
A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomics Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Control populations:
A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Control populations:
A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomics Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Summary:

Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. No segregation analysis given.

PMID: McGee-Lawrence et al 2013 - Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, they generated Axin2(-/-):Runx2(+/-) mice. These double mutant mice had longer skulls than Axin2(-/-) mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2(-/-) mice

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic Patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Frequency of CNVs covering this region in the general population have not been reported.; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given.

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Mouse models:

PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia.

PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis.

PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis.

Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 RUNX2 Eleanor Williams commented on gene: RUNX2: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed).
In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia.
A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID:  23290074, 25311905, 29891876

CNV EVIDENCE:

PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution.

PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed.

PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. No segregation analysis given.

PMID: McGee-Lawrence et al 2013 - Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, they generated Axin2(-/-):Runx2(+/-) mice. These double mutant mice had longer skulls than Axin2(-/-) mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2(-/-) mice

PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic Patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB.

Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs

Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Frequency of CNVs covering this region in the general population have not been reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.122 JAG1 Eleanor Williams Mode of inheritance for gene: JAG1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.121 SIX1 Eleanor Williams Classified gene: SIX1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.121 SIX1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. The group decided to rate Amber due to several unpublished cases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.121 SIX1 Eleanor Williams Gene: six1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.120 PRRX1 Eleanor Williams Classified gene: PRRX1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.120 PRRX1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. The group decided to rate Amber due to several unpublished cases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.120 PRRX1 Eleanor Williams Gene: prrx1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.119 B3GAT3 Eleanor Williams Classified gene: B3GAT3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.119 B3GAT3 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. The group decided to rate amber until there is more evidence for the gene-disease association.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.119 B3GAT3 Eleanor Williams Gene: b3gat3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.118 B3GAT3 Eleanor Williams Mode of inheritance for gene: B3GAT3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.117 PPP1CB Eleanor Williams Phenotypes for gene: PPP1CB were changed from to Noonan syndrome-like disorder with loose anagen hair 2 617506
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.116 PPP1CB Eleanor Williams Classified gene: PPP1CB as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.116 PPP1CB Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. A Noonan syndrome-related gene, but the group decided it should be Amber as there is a less well-evidenced association with craniosynostosis than other Noonan genes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.116 PPP1CB Eleanor Williams Gene: ppp1cb has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.115 PPP1CB Eleanor Williams gene: PPP1CB was added
gene: PPP1CB was added to Craniosynostosis. Sources: Expert list
Mode of inheritance for gene: PPP1CB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: PPP1CB was set to AMBER
Added comment: Adding gene following GMS musculoskeletal specialist test group Webex on 2019-05-13. This is a known Noonan syndrome gene.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.114 SHOC2 Eleanor Williams Classified gene: SHOC2 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.114 SHOC2 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. A Noonan syndrome-related gene, but the group decided it should be Amber as there is a less well-evidenced association.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.114 SHOC2 Eleanor Williams Gene: shoc2 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.113 IFT122 Eleanor Williams Classified gene: IFT122 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.113 IFT122 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. 3 cases now reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.113 IFT122 Eleanor Williams Gene: ift122 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.112 SEC24D Eleanor Williams Phenotypes for gene: SEC24D were changed from Cole-Carpenter syndrome 2 to Cole-Carpenter syndrome 2 616294
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.111 SEC24D Eleanor Williams Publications for gene: SEC24D were set to 25683121
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.110 SEC24D Eleanor Williams Mode of inheritance for gene: SEC24D was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.109 SEC24D Eleanor Williams Classified gene: SEC24D as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.109 SEC24D Eleanor Williams Added comment: Comment on list classification: Upgrading to Amber as there are 3 potentially relevant cases associated with variants in SEC24D. Waiting for the GMS musculoskeletal specialist test group to confirm whether all cases are relevant and it should be upgraded to green or not.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.109 SEC24D Eleanor Williams Gene: sec24d has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.108 SPECC1L Eleanor Williams Phenotypes for gene: SPECC1L were changed from Opitz G/BBB syndrome type 2 to Opitz GBBB syndrome, type II 145410
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.107 SPECC1L Eleanor Williams Classified gene: SPECC1L as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.107 SPECC1L Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.107 SPECC1L Eleanor Williams Gene: specc1l has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.106 HUWE1 Eleanor Williams commented on gene: HUWE1: NOTE: Variants in a specific codon (R110) associated with craniosynostosis. Variants in other codons are associated with intellectual disability.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.106 HUWE1 Eleanor Williams Publications for gene: HUWE1 were set to 25985138; 25590979:29180823
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.105 HUWE1 Eleanor Williams Mode of inheritance for gene: HUWE1 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.104 HUWE1 Eleanor Williams Classified gene: HUWE1 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.104 HUWE1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.104 HUWE1 Eleanor Williams Gene: huwe1 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.103 GNAS Eleanor Williams Classified gene: GNAS as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.103 GNAS Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. Andrew Wilkie of Wessex and West Midlands GLH confirmed unpublished cases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.103 GNAS Eleanor Williams Gene: gnas has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.102 GNAS Eleanor Williams Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.102 GNAS Eleanor Williams Publications for gene: GNAS were set to 19530187; 26340332
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.101 GNAS Eleanor Williams Added comment: Comment on publications: Graul-Neumann et al 2009 - PMID: 19530187
Twigg et al 2015 - PMID: 26340332
Adetayo et al 2015 - PMID: 26267576
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.101 GNAS Eleanor Williams Publications for gene: GNAS were set to 19530187; 26340332
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.100 GNAS Eleanor Williams Classified gene: GNAS as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.100 GNAS Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. Andrew Wilkie of Wessex and West Midlands GLH confirmed several unpublished cases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.100 GNAS Eleanor Williams Gene: gnas has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.99 FAM20C Eleanor Williams Phenotypes for gene: FAM20C were changed from Raine syndrome to Raine syndrome 259775
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.98 FAM20C Eleanor Williams Mode of inheritance for gene: FAM20C was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.97 FAM20C Eleanor Williams Classified gene: FAM20C as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.97 FAM20C Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. Andrew Wilkie of Wessex and West Midlands GLH confirmed several unpublished cases.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.97 FAM20C Eleanor Williams Gene: fam20c has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.96 CYP26B1 Eleanor Williams Mode of inheritance for gene: CYP26B1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.95 CYP26B1 Eleanor Williams Classified gene: CYP26B1 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.95 CYP26B1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. Now 3 cases
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.95 CYP26B1 Eleanor Williams Gene: cyp26b1 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.94 SLC25A24 Eleanor Williams Classified gene: SLC25A24 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.94 SLC25A24 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13. . > 3 cases but same variant in 4 cases and same codon in all, likely because activating mutation rather than founder effect.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.94 SLC25A24 Eleanor Williams Gene: slc25a24 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.93 SLC25A24 Eleanor Williams Mode of inheritance for gene: SLC25A24 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.92 P4HB Eleanor Williams Classified gene: P4HB as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.92 P4HB Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.92 P4HB Eleanor Williams Gene: p4hb has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.91 P4HB Eleanor Williams Phenotypes for gene: P4HB were changed from Cole-Carpenter syndrome 1 to Cole-Carpenter syndrome 1 112240
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.90 P4HB Eleanor Williams Mode of inheritance for gene: P4HB was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.89 ARSB Eleanor Williams Classified gene: ARSB as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.89 ARSB Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.89 ARSB Eleanor Williams Gene: arsb has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.88 ARSB Eleanor Williams Mode of inheritance for gene: ARSB was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.87 JAG1 Eleanor Williams Classified gene: JAG1 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.87 JAG1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.87 JAG1 Eleanor Williams Gene: jag1 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.86 PTPN11 Eleanor Williams Phenotypes for gene: PTPN11 were changed from Noonan syndrome type 1 163950; leopard syndrome 151100 to Noonan syndrome type 1 163950; leopard syndrome 151100
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.85 PTPN11 Eleanor Williams Phenotypes for gene: PTPN11 were changed from Noonan syndrome type 1 - 163950; leopard syndrome 151100 to Noonan syndrome type 1 163950; leopard syndrome 151100
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.84 PTPN11 Eleanor Williams Classified gene: PTPN11 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.84 PTPN11 Eleanor Williams Added comment: Comment on list classification: Upgrading to red to green. This gene causes Noonan syndrome and an an association with craniosynostosis is well documented. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.84 PTPN11 Eleanor Williams Gene: ptpn11 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.83 PTPN11 Eleanor Williams Mode of inheritance for gene: PTPN11 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.82 BRAF Eleanor Williams Mode of inheritance for gene: BRAF was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.81 BRAF Eleanor Williams Classified gene: BRAF as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.81 BRAF Eleanor Williams Added comment: Comment on list classification: Upgrading to red to green. This gene causes Noonan syndrome and an an association with craniosynostosis is well documented. Green rating agreed at the GMS musculoskeletal specialist test group Webex on 2019-05-13.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.81 BRAF Eleanor Williams Gene: braf has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.80 SEC24D Eleanor Williams commented on gene: SEC24D: Associated with Cole-Carpenter syndrome 2 #616294 in OMIM and probable association with SYNDROMIC OSTEOGENESIS IMPERFECTA in Gene2Phenotype.

PMID: 25683121 - Garbes et al 2015 - 7 year old boy with a syndromic form of OI that clinically classified as Cole-Carpenter syndrome, based on the history of multiple pre- and postnatal fractures and the presence of distinct craniofacial malformations. Compound heterozygosity for a SEC24D nonsense mutation (c.613C>T [p.Gln205*]) and for a missense mutation (c.3044C>T [p.Ser1015Phe]). The medaka mutant vbi,
caused by a sec24d nonsense mutation, is characterized by short body length, OI, and craniofacial malformations—including an impaired ossification of the neurocranium (note, Sec24d-null mice are embryonic lethal prior to skeletal development). Fetuses with suspected to be affected by a severe type of OI from second family are likely compound heterozygous for SEC24D mutations c.3044C>T (p.Ser1015Phe) and c.2933A>C (p.Gln978Pro).

PMID: 30462379 - Takeyari et al 2018 - Japanese boy with syndromic OI. His features include a short trunk, and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. He was compound heterogzyous for 2 variants in the SEC24D gene (NM_014822:c.1450C>T:p.Arg484* and c.938G>A:p.Arg313His) .

PMID: 27942778 - Zhang et al 2017 - 2 unrelated families with individuals with osteogenesis imperfecta. Compound heterozygous variants in SEC24D were found in both. Family 1 - c.2723G>A (p. Cys908Tyr) and c.2842T>C (p. Ser948Pro). Family 2 - c.938G>A (p. Arg313His) and c.875C>T (p. Pro292Leu). Proband from family 1 showed skull deformities associated with a broad frontoapical ossification defect, a widened sagittal suture, and Wormian bones. In the proband from family 2 the anterior fontanel was not closed, and he did not have obvious facial dysmorphism.

Consulting with the Genomics England Team with respect to the relevance to craniosynostosis of these phenotypes.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.80 SEC24D Eleanor Williams Added comment: Comment on publications: PMID: 25683121 - Garbes et al (2015)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.80 SEC24D Eleanor Williams Publications for gene: SEC24D were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.79 B3GAT3 Eleanor Williams commented on gene: B3GAT3: PMID: 28771243 - Yauy et al 2018 - six patients from four unrelated consanguineous families, all from Morocco. All sequenced patients showed a unique homozygous mutation of c.667G >A, p.Gly223Ser in the B3GAT3 gene. 3 patients from 2 families showed craniosynostosis.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.79 SHOC2 Eleanor Williams Added comment: Comment on publications: PMID: 25123707 - Takenouchi et al 2014
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.79 SHOC2 Eleanor Williams Publications for gene: SHOC2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.78 ISCA-37420-Loss Eleanor Williams Phenotypes for Region: ISCA-37420-Loss were changed from to Koolen-de Vries/KANSL haploinsufficiency syndrome.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.77 ISCA-37420-Loss Eleanor Williams Publications for Region: ISCA-37420-Loss were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.76 KANSL1 Eleanor Williams Added comment: Comment on publications: Zollino et al 2015 - PMID:26424144
Dubourg et al 2011 - PMID:21094706
Tan et al 2009 - PMID: 19447831
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.76 KANSL1 Eleanor Williams Publications for gene: KANSL1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.75 KANSL1 Eleanor Williams Classified gene: KANSL1 as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.75 KANSL1 Eleanor Williams Added comment: Comment on list classification: No evidence that variants in KANSL1 cause craniosynostosis, however reports that 17q21.21 deletions covering KANSL1 are associated with craniosynostosis
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.75 KANSL1 Eleanor Williams Gene: kansl1 has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.74 SCARF2 Eleanor Williams Publications for gene: SCARF2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.73 ADAMTSL4 Eleanor Williams Publications for gene: ADAMTSL4 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 AHDC1 Eleanor Williams Added phenotypes Xia-Gibbs syndrome 615829 for gene: AHDC1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 HUWE1 Eleanor Williams Added phenotypes X-linked intellectual disability with CSS for gene: HUWE1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SCARF2 Eleanor Williams Added phenotypes Van den Ende-Gupta syndrome for gene: SCARF2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 TCOF1 Eleanor Williams Added phenotypes Treacher-Collins syndrome for gene: TCOF1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 NOG Eleanor Williams Added phenotypes Tarsal-carpal coalition syndrome; Stapes ankylosis with broad thumb and toes (Teunissen-Cremers syndrome); Brachydactyly type B2; Multiple synostosis syndrome; Symphalangism, proximal for gene: NOG
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 CHST3 Eleanor Williams Added phenotypes Spondyloepiphyseal dysplasia with congenital joint dislocations for gene: CHST3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 GPC3 Eleanor Williams Added phenotypes Simpson-Golabi-Behmel syndrome for gene: GPC3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SKI Eleanor Williams Added phenotypes Shprintzen-Goldberg syndrome 182212 for gene: SKI
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IFT140 Eleanor Williams Added phenotypes Short-rib thoracic dysplasia with or without polydactyly; asphyxiating thoracic dysplasia (ATD,Jeune) for gene: IFT140
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ATR Eleanor Williams Added phenotypes Seckel syndrome 1 210600 for gene: ATR
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ESCO2 Eleanor Williams Added phenotypes Roberts syndrome; SC phocomelia syndrome for gene: ESCO2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IGF1R Eleanor Williams Added phenotypes Resistance to insulin-like growth factor I for gene: IGF1R
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 CTSK Eleanor Williams Added phenotypes Pycnodysostosis 265800 for gene: CTSK
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 GNAS Eleanor Williams Added phenotypes pseudohypoparathyroidism type 1a 103580 for gene: GNAS
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SOX10 Eleanor Williams Added phenotypes Hirschsprung disease; Waardenburg syndrome; Peripheral demyelinating neuropathy; central dysmyelination for gene: SOX10
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SPECC1L Eleanor Williams Added phenotypes Opitz G/BBB syndrome type 2 for gene: SPECC1L
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 AXIN2 Eleanor Williams Added phenotypes Oligodontia-colorectal cancer syndrome 604025 for gene: AXIN2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SHOC2 Eleanor Williams Added phenotypes Noonan-like syndrome with loose anagen hair 607721 for gene: SHOC2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 BRAF Eleanor Williams Added phenotypes cardiofaciocutaneous syndrome type 115150; Noonan syndrome type 7 613706 for gene: BRAF
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 KRAS Eleanor Williams Added phenotypes Noonan syndrome type 3 609942; cardiofaciocutaneous syndrome type 2 615278 for gene: KRAS
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 PTPN11 Eleanor Williams Added phenotypes Noonan syndrome type 1 - 163950; leopard syndrome 151100 for gene: PTPN11
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SLC3A2 Eleanor Williams Added phenotypes no disorder assigned on OMIM - possible role in immune function based on mouse studies. for gene: SLC3A2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 LMX1B Eleanor Williams Added phenotypes Nail-patella syndrome - LOF for gene: LMX1B
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ARSB Eleanor Williams Added phenotypes Mucopolysaccharidosis VI (MPS6) 253200 for gene: ARSB
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IDS Eleanor Williams Added phenotypes Mucopolysaccharidosis II (MPS2, Hunter syndrome) 309900 for gene: IDS
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IDUA Eleanor Williams Added phenotypes Mucopolysaccharidosis Ih/s (Hurler syndrome) 607014; 607016 for gene: IDUA
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 GNPTAB Eleanor Williams Added phenotypes Mucolipidosis II alpha/beta(I cell disease) 252500 for gene: GNPTAB
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ZEB2 Eleanor Williams Added phenotypes Mowat-Wilson syndrome 235730 for gene: ZEB2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 BMP4 Eleanor Williams Added phenotypes orofacial cleft; Microphthalmia, syndromic type 6 607932 for gene: BMP4
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 COLEC10 Eleanor Williams Added phenotypes MC syndrome 3 248340 for gene: COLEC10
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 NFIX Eleanor Williams Added phenotypes Marshall-Smith syndrome for gene: NFIX
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 FBN1 Eleanor Williams Added phenotypes Marfan syndrome for gene: FBN1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 TGFBR2 Eleanor Williams Added phenotypes Loeys-Dietz syndrome 2 610168 for gene: TGFBR2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 TGFBR1 Eleanor Williams Added phenotypes Loeys-Dietz syndrome 1 609192 for gene: TGFBR1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 FLNB Eleanor Williams Added phenotypes spondylo-carpel-tarsel dysplasia; Larsen syndrome (dominant); atelsteogenesis type 1/3 for gene: FLNB
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 KANSL1 Eleanor Williams gene: KANSL1 was added
gene: KANSL1 was added to Craniosynostosis. Sources:
Mode of inheritance for gene: KANSL1 was set to
Phenotypes for gene: KANSL1 were set to Koolen-de Vries/KANSL haploinsufficiency syndrome.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 KAT6B Eleanor Williams Added phenotypes KAT6B-related disorders for gene: KAT6B
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 KDM6A Eleanor Williams Added phenotypes Kabuki syndrome 2 300867 for gene: KDM6A
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 KMT2D Eleanor Williams Added phenotypes Kabuki syndrome 147920 for gene: KMT2D
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 CEP120 Eleanor Williams Added phenotypes short rib thoracic dysplasia 13 +/- polydactyly; Joubert syndrome 31 for gene: CEP120
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ABCC9 Eleanor Williams Added phenotypes hypertrichotic osteochondrodysplasia, Cantu syndrome 239850 for gene: ABCC9
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 STAT3 Eleanor Williams Added phenotypes Hyper IgE recurrent infection syndrome 147060 for gene: STAT3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 EDNRB Eleanor Williams Added phenotypes Waardenburg syndrome; ABCD syndrome; Hirschprung disease for gene: EDNRB
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 CCBE1 Eleanor Williams Added phenotypes Hennekam-lymphangiectasia-lymphedema syndrome 1 235510 for gene: CCBE1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 GLI3 Eleanor Williams Added phenotypes Greig cephalopolysyndactyly syndrome 175700 for gene: GLI3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ALX1 Eleanor Williams Added phenotypes Frontonasal dysplasia type 3 for gene: ALX1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ALX3 Eleanor Williams Added phenotypes Frontonasal dysplasia type 1 (frontorhiny) for gene: ALX3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SH3PXD2B Eleanor Williams Added phenotypes Borrone dermato-cardio-skeletal syndrome; Frank-ter-har 249420 for gene: SH3PXD2B
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SLC25A24 Eleanor Williams Added phenotypes Fontaine progeroid syndrome 612289; Gorlin-Chaudhry-Moss for gene: SLC25A24
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ADAMTSL4 Eleanor Williams Added phenotypes Ectopia lentis 225200/225100 for gene: ADAMTSL4
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 B3GAT3 Eleanor Williams Added phenotypes Craniosynostosis and bone fragility for gene: B3GAT3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 ZIC1 Eleanor Williams Added phenotypes Craniosynostosis 6 616602 for gene: ZIC1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 RUNX2 Eleanor Williams Added phenotypes Craniosynostosis for gene: RUNX2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 EFNB1 Eleanor Williams Added phenotypes Craniofrontonasal syndrome 304110 for gene: EFNB1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 PAX3 Eleanor Williams Added phenotypes Waardenburg syndrome; Craniofacial-deafness-hand syndrome for gene: PAX3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 WDR19 Eleanor Williams Added phenotypes Cranioectodermal dysplasia type 4 614378 for gene: WDR19
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IFT43 Eleanor Williams Added phenotypes Short-rib thoracic dysplasia 18 with polydactyly 617866; Cranioectodermal dysplasia type 3 614099 for gene: IFT43
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 WDR35 Eleanor Williams Added phenotypes Cranioectodermal dysplasia type 2 (Sensenbrenner syndrome) 613610 for gene: WDR35
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IFT122 Eleanor Williams Added phenotypes Cranioectodermal dysplasia type 1 218330 for gene: IFT122
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 FGF3 Eleanor Williams Added phenotypes congenital deafness with inner ear agenesis, microtia and microdontia for gene: FGF3
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 SEC24D Eleanor Williams Added phenotypes Cole-Carpenter syndrome 2 for gene: SEC24D
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 P4HB Eleanor Williams Added phenotypes Cole-Carpenter syndrome 1 for gene: P4HB
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 CRTAP Eleanor Williams Added phenotypes Cole Carpenter for gene: CRTAP
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IMPAD1 Eleanor Williams Added phenotypes Chondrodysplasia with joint dislocations, GPAPP type for gene: IMPAD1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 TMCO1 Eleanor Williams Added phenotypes MR syndrome; Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism; skeletal anomalies for gene: TMCO1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 RAB23 Eleanor Williams Added phenotypes Carpenter syndrome 201000 for gene: RAB23
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 MEGF8 Eleanor Williams Added phenotypes Carpenter 2 614976 for gene: MEGF8
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 CD96 Eleanor Williams Added phenotypes C syndrome for gene: CD96
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 FREM1 Eleanor Williams Added phenotypes Manitoba oculotrichoanal syndrome; bifid nose; trigonocephaly for gene: FREM1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 BBS9 Eleanor Williams Added phenotypes Bardet-Biedl syndrome 9 615986 for gene: BBS9
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 RECQL4 Eleanor Williams Added phenotypes Baller-Gerold syndrome 218600 for gene: RECQL4
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 OSTM1 Eleanor Williams Added phenotypes AR osteopetrosis 5 for gene: OSTM1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 POR Eleanor Williams Added phenotypes Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750 for gene: POR
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 JAG1 Eleanor Williams Added phenotypes Alagille syndrome for gene: JAG1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 TLK2 Eleanor Williams Added phenotypes AD MR type 57 - 618050 for gene: TLK2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 IHH Eleanor Williams Added phenotypes chr2q35dup syndrome 185900; Acrocapitofermoral dysplasia 607778; bracydactyly type A1 112500 for gene: IHH
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 TWIST2 Eleanor Williams Added phenotypes Focal facial dermal dysplasia 3, Setleis type; Barber-Say syndrome; Ablepharon-macrostomia syndrome for gene: TWIST2
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 COLEC11 Eleanor Williams Added phenotypes 3MC syndrome 2 265050 for gene: COLEC11
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 MASP1 Eleanor Williams Added phenotypes 3MC syndrome 1 257920 for gene: MASP1
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.71 TLK2 Eleanor Williams Added comment: Comment on publications: https://doi.org/10.1016/j.ajhg.2018.04.014 is PMID: 29861108
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.71 TLK2 Eleanor Williams Publications for gene: TLK2 were set to 27479843; https://doi.org/10.1016/j.ajhg.2018.04.014
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.70 ALPL Eleanor Williams Added comment: Comment on publications: Collmann et al is PMID:18769927
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.70 ALPL Eleanor Williams Publications for gene: ALPL were set to 19232125
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.69 CRTAP Eleanor Williams Publications for gene: CRTAP were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.68 ISCA-37420-Loss Eleanor Williams Classified Region: ISCA-37420-Loss as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.68 ISCA-37420-Loss Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber as some evidence of association of the CNV loss with craniosynostosis. Will discuss on Webex with GMS Musculoskeletal test group
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.68 ISCA-37420-Loss Eleanor Williams Region: isca-37420-loss has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.67 ARSB Eleanor Williams Publications for gene: ARSB were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.66 SPECC1L Eleanor Williams Publications for gene: SPECC1L were set to 25412741
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.65 SPECC1L Eleanor Williams Added comment: Comment on publications: Kruska et al 2015 PMID: 25412741, Bhoj et al 2015 PMID: 26111080
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.65 SPECC1L Eleanor Williams Publications for gene: SPECC1L were set to 25412741
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.64 SLC25A24 Eleanor Williams Added comment: Comment on publications: Writzl et al 2017 PMID: 29100094
Ehmke et al 2017 PMID: 29100093
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.64 SLC25A24 Eleanor Williams Publications for gene: SLC25A24 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.63 PTPN11 Eleanor Williams Added comment: Comment on publications: Ueda et al 2017 PMID: 28650561
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.63 PTPN11 Eleanor Williams Publications for gene: PTPN11 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.62 P4HB Eleanor Williams Added comment: Comment on publications: Rauch et al 2015 PMID: 25683117
Ouyang et al 2017 PMID: 29384951
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.62 P4HB Eleanor Williams Publications for gene: P4HB were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.61 JAG1 Eleanor Williams Added comment: Comment on publications: Adding PMID: 29530693 - Narro-Donate et al 2018
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.61 JAG1 Eleanor Williams Publications for gene: JAG1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.60 HUWE1 Eleanor Williams Added comment: Comment on publications: Adding Moortgat et al 2018 PMID:29180823
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.60 HUWE1 Eleanor Williams Publications for gene: HUWE1 were set to 25985138; 25590979
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.59 HUWE1 Eleanor Williams Publications for gene: HUWE1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.58 FAM20C Eleanor Williams Phenotypes for gene: FAM20C were changed from to Raine syndrome
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.57 FAM20C Eleanor Williams Publications for gene: FAM20C were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.56 CYP26B1 Eleanor Williams Publications for gene: CYP26B1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.55 CYP26B1 Eleanor Williams commented on gene: CYP26B1: Laue et al 2011 PMID: 22019272 - 2 families.
Morton et al 2016 PMID: 27410456
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.55 BRAF Eleanor Williams Publications for gene: BRAF were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.54 B3GAT3 Eleanor Williams Publications for gene: B3GAT3 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.53 ISCA-37420-Loss Eleanor Williams commented on Region: ISCA-37420-Loss: PMID: 26424144 - Zollino et al 2015 – 1 patient with craniosynostosis and 17q21.31 deletion (patient 28). Other patients with variants in KANSL1 but no craniosynostosis reported.

PMID: 21094706 - Dubourg et al 2011 – report 2 patients with Scaphocephaly and 17q21.31 deletion

PMID: 19447831 -Tan et al 2009 – KANSL1 called KIAA1267 in this paper. 5 patients with mixture of brachycephaly, dolichocephaly, scaphocephaly, positional plagiocephaly.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.53 ISCA-37420-Loss Eleanor Williams edited their review of Region: ISCA-37420-Loss: Added comment: Review on behalf of Tracy Lester and Andrew Wilkie: Zollino report 2 cases with scaphocephaly or sagittal CSS.; Changed rating: AMBER; Changed phenotypes: Koolen-de Vries/KANSL haploinsufficiency syndrome.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.53 ISCA-37420-Loss Eleanor Williams commented on Region: ISCA-37420-Loss
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.53 ISCA-37420-Loss Eleanor Williams Region: ISCA-37420-Loss was added
Region: ISCA-37420-Loss was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for Region: ISCA-37420-Loss was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.52 NFIA Tracy Lester reviewed gene: NFIA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.51 NFIA Eleanor Williams reviewed gene: NFIA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.50 NFIA Eleanor Williams gene: NFIA was added
gene: NFIA was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: NFIA was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.49 KANSL1-AS1 Eleanor Williams Classified gene: KANSL1-AS1 as No list
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.49 KANSL1-AS1 Eleanor Williams Added comment: Comment on list classification: Removing this gene from the panel. Incorrectly added from list that Tracy Lester sent. Gene should have been KANSL1 - ENSG00000120071, but this is part of a larger duplication in one family so waiting for discussion with clinical team about how to best represent this on the panel.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.49 KANSL1-AS1 Eleanor Williams Gene: kansl1-as1 has been removed from the panel.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.48 ISCA-37441-Loss Eleanor Williams Source NHS GMS was added to Region: ISCA-37441-Loss.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss: This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Region submitted: 11p11.2del (ISCA-37441-Loss); Suggested initial gene rating: green
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ISCA-37441-Loss Eleanor Williams reviewed Region: ISCA-37441-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: 15852040, 16319823, 20140962; Phenotypes: Potocki-Shaffer syndrome, multiple exostoses, biparietal foramina, intellectual disability, strabismus, minor craniofacial anomalies, myopia, ophthalmologic anomalies, 601224, mental retardation, enlarged anterior fontanel, genital abnormalities in males, parietal foramina, developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ZIC1 Tracy Lester reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 26340333; Phenotypes: Craniosynostosis 6 - 616602; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ZEB2 Tracy Lester reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26097173, 25123255, 24300291, 18076118; Phenotypes: Mowat-Wilson syndrome - 235730; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 WDR35 Tracy Lester reviewed gene: WDR35: Rating: GREEN; Mode of pathogenicity: ; Publications: 24123776; Phenotypes: Cranioectodermal dysplasia type 2 (Sensenbrenner syndrome) - 613610; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 WDR19 Tracy Lester reviewed gene: WDR19: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Cranioectodermal dysplasia type 4- 614378; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TWIST2 Tracy Lester reviewed gene: TWIST2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Ablepharon-macrostomia syndrome, Barber-Say syndrome, Focal facial dermal dysplasia 3, Setleis type; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TWIST1 Tracy Lester reviewed gene: TWIST1: Rating: GREEN; Mode of pathogenicity: ; Publications: 8988166, 8988167; Phenotypes: Saethre-Chotzen syndrome, 101400, Saethre-Chotzen syndrome with eyelid anomalies, 101400, Craniosynostosis, type 1, 123100, Robinow-Sorauf syndrome, 180750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TMCO1 Tracy Lester reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism, skeletal anomalies and MR syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TLK2 Tracy Lester reviewed gene: TLK2: Rating: GREEN; Mode of pathogenicity: ; Publications: 27479843, https://doi.org/10.1016/j.ajhg.2018.04.014; Phenotypes: AD MR type 57 - 618050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TICRR Tracy Lester reviewed gene: TICRR: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: coronal craniosynostosis, cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TGFBR2 Tracy Lester reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 15731757; Phenotypes: Loeys-Dietz syndrome 2 - 610168; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TGFBR1 Tracy Lester reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 15731757; Phenotypes: Loeys-Dietz syndrome 1 - 609192; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TCOF1 Tracy Lester reviewed gene: TCOF1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Treacher-Collins syndrome; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 TCF12 Tracy Lester reviewed gene: TCF12: Rating: GREEN; Mode of pathogenicity: ; Publications: 23354436, 25271085, 24736737; Phenotypes: Craniosynostosis 3, 615314, Craniosynostosis 3; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 STAT3 Tracy Lester reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20159255; Phenotypes: Hyper IgE recurrent infection syndrome - 147060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SPECC1L Tracy Lester reviewed gene: SPECC1L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Opitz G/BBB syndrome type 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SOX6 Tracy Lester reviewed gene: SOX6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: No disease association on OMIM; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SOX10 Tracy Lester reviewed gene: SOX10: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, Hirschsprung disease; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SMO Tracy Lester reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: 27236920; Phenotypes: Curry-Jones syndrome, somatic mosaic, 601707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SMAD6 Tracy Lester reviewed gene: SMAD6: Rating: GREEN; Mode of pathogenicity: ; Publications: 27606499, 23438589, 28808027, 28659821; Phenotypes: metopic synostosis, sagittal synostosis, {Craniosynostosis 7, susceptibility to} 617439; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SLC3A2 Tracy Lester reviewed gene: SLC3A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: no disorder assigned on OMIM - possible role in immune function based on mouse studies.; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SLC25A24 Tracy Lester reviewed gene: SLC25A24: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fontaine progeroid syndrome -612289, Gorlin-Chaudhry-Moss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SKI Tracy Lester reviewed gene: SKI: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 23023332, 23103230, 24736733; Phenotypes: Shprintzen-Goldberg syndrome - 182212; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SIX1 Tracy Lester reviewed gene: SIX1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: sagittal synostosis, multi-suture synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SHOC2 Tracy Lester reviewed gene: SHOC2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan-like syndrome with loose anagen hair- 607721; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SH3PXD2B Tracy Lester reviewed gene: SH3PXD2B: Rating: AMBER; Mode of pathogenicity: ; Publications: 23140272; Phenotypes: Frank-ter-har 249420, Borrone dermato-cardio-skeletal syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SEC24D Tracy Lester reviewed gene: SEC24D: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Cole-Carpenter syndrome 2; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SCN4A Tracy Lester reviewed gene: SCN4A: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 SCARF2 Tracy Lester reviewed gene: SCARF2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Van den Ende-Gupta syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 RUNX2 Tracy Lester reviewed gene: RUNX2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20683987, 23307468, 23348268; Phenotypes: Craniosynostosis - not on OMIM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 RSPRY1 Tracy Lester reviewed gene: RSPRY1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 RECQL4 Tracy Lester reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: 24635570; Phenotypes: Baller-Gerold syndrome - 218600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 RAB23 Tracy Lester reviewed gene: RAB23: Rating: GREEN; Mode of pathogenicity: ; Publications: 17503333; Phenotypes: Carpenter syndrome, 201000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 PTPRD Tracy Lester reviewed gene: PTPRD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 PTPN11 Tracy Lester reviewed gene: PTPN11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Noonan syndrome type 1 - 163950, leopard syndrome - 151100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 PRRX1 Tracy Lester reviewed gene: PRRX1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: craniosynostosis, various combinations of sutures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 POR Tracy Lester reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: ; Publications: 14758361; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis: 201750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 PHEX Tracy Lester reviewed gene: PHEX: Rating: GREEN; Mode of pathogenicity: ; Publications: 17551721, 19242361; Phenotypes: X-linked hypophosphataemic rickets; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 PAX3 Tracy Lester reviewed gene: PAX3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Craniofacial-deafness-hand syndrome, Waardenburg syndrome; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 P4HB Tracy Lester reviewed gene: P4HB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cole-Carpenter syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 OSTM1 Tracy Lester reviewed gene: OSTM1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: AR osteopetrosis 5; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 NOG Tracy Lester reviewed gene: NOG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Tarsal-carpal coalition syndrome, Multiple synostosis syndrome, Stapes ankylosis with broad thumb and toes (Teunissen-Cremers syndrome), Symphalangism, proximal,, Brachydactyly type B2. ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 NFIX Tracy Lester reviewed gene: NFIX: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Marshall-Smith syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 MSX2 Tracy Lester reviewed gene: MSX2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 8106171, 23949913, 23918290; Phenotypes: Craniosynostosis, type 2, 604757, Parietal foramina 1, 168500, Parietal foramina with cleidocranial dysplasia, 168550, Craniosynostosis, MSX2-related craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 MEGF8 Tracy Lester reviewed gene: MEGF8: Rating: GREEN; Mode of pathogenicity: ; Publications: 23063620; Phenotypes: Carpenter 2 614976; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 MASP1 Tracy Lester reviewed gene: MASP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: 3MC syndrome 1 - 257920; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 LRP5 Tracy Lester reviewed gene: LRP5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 LMX1B Tracy Lester reviewed gene: LMX1B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Nail-patella syndrome - LOF; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 KRAS Tracy Lester reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 19396835, 22488932; Phenotypes: Noonan syndrome type 3 - 609942, cardiofaciocutaneous syndrome type 2 - 615278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 KMT2D Tracy Lester reviewed gene: KMT2D: Rating: GREEN; Mode of pathogenicity: ; Publications: 20672944, 21280141; Phenotypes: Kabuki syndrome 147920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 KDM6A Tracy Lester reviewed gene: KDM6A: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Kabuki syndrome 2 - 300867; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 KAT6B Tracy Lester reviewed gene: KAT6B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: KAT6B-related disorders; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 KAT6A Tracy Lester reviewed gene: KAT6A: Rating: GREEN; Mode of pathogenicity: ; Publications: 25728775, 25728777; Phenotypes: Mental retardation (with Craniosynostosis), 616268; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 KANSL1-AS1 Tracy Lester reviewed gene: KANSL1-AS1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Koolen-de Vries/KANSL haploinsufficiency syndrome.; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 JAG1 Tracy Lester reviewed gene: JAG1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Alagille syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IRX5 Tracy Lester reviewed gene: IRX5: Rating: AMBER; Mode of pathogenicity: ; Publications: 22581230; Phenotypes: Hamamy syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IMPAD1 Tracy Lester reviewed gene: IMPAD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Chondrodysplasia with joint dislocations, GPAPP type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IL11RA Tracy Lester reviewed gene: IL11RA: Rating: GREEN; Mode of pathogenicity: ; Publications: 21741611, 24002815, 24498618; Phenotypes: Craniosynostosis and dental anomalies, 614188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IHH Tracy Lester reviewed gene: IHH: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 25692887, 21167467; Phenotypes: Acrocapitofermoral dysplasia 607778, bracydactyly type A1 (112500), chr2q35dup syndrome(185900); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IGF1R Tracy Lester reviewed gene: IGF1R: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Resistance to insulin-like growth factor I; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IFT43 Tracy Lester reviewed gene: IFT43: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Cranioectodermal dysplasia type 3 - 614099, Short-rib thoracic dysplasia 18 with polydactyly -617866; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IFT140 Tracy Lester reviewed gene: IFT140: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Short-rib thoracic dysplasia with or without polydactyly, asphyxiating thoracic dysplasia (ATD,Jeune); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IFT122 Tracy Lester reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: ; Publications: 24689072, 20493458; Phenotypes: Cranioectodermal dysplasia type 1 - 218330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IDUA Tracy Lester reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: ; Publications: 23917744; Phenotypes: Mucopolysaccharidosis Ih/s (Hurler syndrome) 607014, 607016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 IDS Tracy Lester reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: ; Publications: 15314824; Phenotypes: Mucopolysaccharidosis II (MPS2, Hunter syndrome) 309900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 HUWE1 Tracy Lester reviewed gene: HUWE1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: X-linked intellectual disability with CSS; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 GPC3 Tracy Lester reviewed gene: GPC3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Simpson-Golabi-Behmel syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 GNPTAB Tracy Lester reviewed gene: GNPTAB: Rating: GREEN; Mode of pathogenicity: ; Publications: 24891900; Phenotypes: Mucolipidosis II alpha/beta(I cell disease) - 252500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 GNAS Tracy Lester reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: ; Publications: 19530187, 26340332; Phenotypes: pseudohypoparathyroidism type 1a 103580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 GLI3 Tracy Lester reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: ; Publications: 21326280, 20583172; Phenotypes: Greig cephalopolysyndactyly syndrome, 175700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FREM1 Tracy Lester reviewed gene: FREM1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: bifid nose, Manitoba oculotrichoanal syndrome, trigonocephaly; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FLNB Tracy Lester reviewed gene: FLNB: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Larsen syndrome (dominant), atelsteogenesis type 1/3, spondylo-carpel-tarsel dysplasia; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FLNA Tracy Lester reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 25873011; Phenotypes: frontometaphyseal dysplasia, oto-palato-digital syndromes, melnick-needles syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FGFR3 Tracy Lester reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 9042914, 7493034; Phenotypes: Muenke syndrome, Crouzon syndrome with acanthosis nigricans; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FGFR2 Tracy Lester reviewed gene: FGFR2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 7719344, 7987400, 7719345, 8696350, 22387015; Phenotypes: Crouzon syndrome, 123500, Jackson-Weiss syndrome, 123150, Beare-Stevenson cutis gyrata syndrome, 123790, Pfeiffer syndrome, 101600, Apert syndrome, 101200, Saethre-Chotzen, Craniosynostosis, nonspecific syndrome, 101400, Gastric cance, Craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FGFR1 Tracy Lester reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 7874169, 15625620; Phenotypes: Craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FGF9 Tracy Lester reviewed gene: FGF9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FGF3 Tracy Lester reviewed gene: FGF3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: congenital deafness with inner ear agenesis, microtia and microdontia; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FBN1 Tracy Lester reviewed gene: FBN1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Marfan syndrome; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 FAM20C Tracy Lester reviewed gene: FAM20C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Raine syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ESCO2 Tracy Lester reviewed gene: ESCO2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Roberts syndrome, SC phocomelia syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ERF Tracy Lester reviewed gene: ERF: Rating: GREEN; Mode of pathogenicity: ; Publications: 26097063, 23354439; Phenotypes: Craniosynostosis 4, 600775; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 EFNB1 Tracy Lester reviewed gene: EFNB1: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: 15166289, 23335590, 15124102; Phenotypes: Craniofrontonasal syndrome, 304110; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 EFNA4 Tracy Lester reviewed gene: EFNA4: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 EDNRB Tracy Lester reviewed gene: EDNRB: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Hirschprung disease, ABCD syndrome, Waardenburg syndrome; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 DHRS3 Tracy Lester reviewed gene: DHRS3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: coronal craniosynostosis, septal heart defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CYP26B1 Tracy Lester reviewed gene: CYP26B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomalies, 614416; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CTSK Tracy Lester reviewed gene: CTSK: Rating: GREEN; Mode of pathogenicity: ; Publications: 21968522, 23175007; Phenotypes: Pycnodysostosis, 265800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CRTAP Tracy Lester reviewed gene: CRTAP: Rating: AMBER; Mode of pathogenicity: ; Publications: 25604815; Phenotypes: Cole Carpenter; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 COLEC11 Tracy Lester reviewed gene: COLEC11: Rating: GREEN; Mode of pathogenicity: ; Publications: 21258343; Phenotypes: 3MC syndrome 2, 265050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 COLEC10 Tracy Lester reviewed gene: COLEC10: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: MC syndrome 3 - 248340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CHST3 Tracy Lester reviewed gene: CHST3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Spondyloepiphyseal dysplasia with congenital joint dislocations; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CEP120 Tracy Lester reviewed gene: CEP120: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Joubert syndrome 31, short rib thoracic dysplasia 13 +/- polydactyly; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CDC45 Tracy Lester reviewed gene: CDC45: Rating: GREEN; Mode of pathogenicity: ; Publications: 25985138; Phenotypes: Coronal synostosis, Meier-Gorlin syndrome 7, 617063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CD96 Tracy Lester reviewed gene: CD96: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: C syndrome; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 CCBE1 Tracy Lester reviewed gene: CCBE1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Hennekam-lymphangiectasia-lymphedema syndrome 1 - 235510; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 BRAF Tracy Lester reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: ; Publications: Ueda et al 2017 ; Phenotypes: Noonan syndrome type 7 - 613706, cardiofaciocutaneous syndrome type - 115150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 BMP4 Tracy Lester reviewed gene: BMP4: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Microphthalmia, syndromic type 6- 607932, orofacial cleft; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 BBS9 Tracy Lester reviewed gene: BBS9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Bardet-Biedl syndrome 9, 615986; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 B3GAT3 Tracy Lester reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: ; Publications: Yauy Genet Med 20:269 (2018); Phenotypes: Craniosynostosis and bone fragility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 AXIN2 Tracy Lester reviewed gene: AXIN2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Oligodontia-colorectal cancer syndrome, 604025; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ATR Tracy Lester reviewed gene: ATR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Seckel syndrome 1 - 210600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ASXL1 Tracy Lester reviewed gene: ASXL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 21706002; Phenotypes: Bohring-Opitz syndrome, 605039; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ARSB Tracy Lester reviewed gene: ARSB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Mucopolysaccharidosis VI (MPS6) 253200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ALX4 Tracy Lester reviewed gene: ALX4: Rating: GREEN; Mode of pathogenicity: ; Publications: 22829454, 29681084, 29215649; Phenotypes: Parietal foramina, Parietal foramina 2, (AD), 609597, Frontonasal dysplasia 2, (AR), 613451; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ALX3 Tracy Lester reviewed gene: ALX3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Frontonasal dysplasia type 1 (frontorhiny); Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ALX1 Tracy Lester reviewed gene: ALX1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Frontonasal dysplasia type 3; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ALPL Tracy Lester reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: ; Publications: 19232125, Collmann et al 2009 Childs Nerve Syst 25:217-223.; Phenotypes: Hypophosphatasia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 AHDC1 Tracy Lester reviewed gene: AHDC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Xia-Gibbs syndrome - 615829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ADAMTSL4 Tracy Lester reviewed gene: ADAMTSL4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Ectopia lentis -225200/225100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 ABCC9 Tracy Lester reviewed gene: ABCC9: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: hypertrichotic osteochondrodysplasia - 239850 (Cantu syndrome); Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ZIC1 Eleanor Williams reviewed gene: ZIC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ZEB2 Eleanor Williams reviewed gene: ZEB2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 WDR35 Eleanor Williams reviewed gene: WDR35: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 WDR19 Eleanor Williams reviewed gene: WDR19: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TWIST2 Eleanor Williams reviewed gene: TWIST2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TWIST1 Eleanor Williams reviewed gene: TWIST1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TMCO1 Eleanor Williams reviewed gene: TMCO1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TLK2 Eleanor Williams reviewed gene: TLK2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TICRR Eleanor Williams reviewed gene: TICRR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TGFBR2 Eleanor Williams reviewed gene: TGFBR2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TGFBR1 Eleanor Williams reviewed gene: TGFBR1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TCOF1 Eleanor Williams reviewed gene: TCOF1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 TCF12 Eleanor Williams reviewed gene: TCF12: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 STAT3 Eleanor Williams reviewed gene: STAT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SPECC1L Eleanor Williams reviewed gene: SPECC1L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SOX6 Eleanor Williams reviewed gene: SOX6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SOX10 Eleanor Williams reviewed gene: SOX10: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SMO Eleanor Williams reviewed gene: SMO: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SMAD6 Eleanor Williams reviewed gene: SMAD6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SLC3A2 Eleanor Williams reviewed gene: SLC3A2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SLC25A24 Eleanor Williams reviewed gene: SLC25A24: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SKI Eleanor Williams reviewed gene: SKI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SIX1 Eleanor Williams reviewed gene: SIX1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SHOC2 Eleanor Williams reviewed gene: SHOC2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SH3PXD2B Eleanor Williams reviewed gene: SH3PXD2B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SEC24D Eleanor Williams reviewed gene: SEC24D: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SCN4A Eleanor Williams reviewed gene: SCN4A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 SCARF2 Eleanor Williams reviewed gene: SCARF2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 RUNX2 Eleanor Williams reviewed gene: RUNX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 RSPRY1 Eleanor Williams reviewed gene: RSPRY1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 RECQL4 Eleanor Williams reviewed gene: RECQL4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 RAB23 Eleanor Williams reviewed gene: RAB23: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 PTPRD Eleanor Williams reviewed gene: PTPRD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 PTPN11 Eleanor Williams reviewed gene: PTPN11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 PRRX1 Eleanor Williams reviewed gene: PRRX1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 POR Eleanor Williams reviewed gene: POR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 PHEX Eleanor Williams reviewed gene: PHEX: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 PAX3 Eleanor Williams reviewed gene: PAX3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 P4HB Eleanor Williams reviewed gene: P4HB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 OSTM1 Eleanor Williams reviewed gene: OSTM1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 NOG Eleanor Williams reviewed gene: NOG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 NFIX Eleanor Williams reviewed gene: NFIX: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 MSX2 Eleanor Williams reviewed gene: MSX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 MEGF8 Eleanor Williams reviewed gene: MEGF8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 MASP1 Eleanor Williams reviewed gene: MASP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 LRP5 Eleanor Williams reviewed gene: LRP5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 LMX1B Eleanor Williams reviewed gene: LMX1B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 KRAS Eleanor Williams reviewed gene: KRAS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 KMT2D Eleanor Williams reviewed gene: KMT2D: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 KDM6A Eleanor Williams reviewed gene: KDM6A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 KAT6B Eleanor Williams reviewed gene: KAT6B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 KAT6A Eleanor Williams reviewed gene: KAT6A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 KANSL1-AS1 Eleanor Williams reviewed gene: KANSL1-AS1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 JAG1 Eleanor Williams reviewed gene: JAG1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IRX5 Eleanor Williams reviewed gene: IRX5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IMPAD1 Eleanor Williams reviewed gene: IMPAD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IL11RA Eleanor Williams reviewed gene: IL11RA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IHH Eleanor Williams reviewed gene: IHH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IGF1R Eleanor Williams reviewed gene: IGF1R: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IFT43 Eleanor Williams reviewed gene: IFT43: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IFT140 Eleanor Williams reviewed gene: IFT140: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IFT122 Eleanor Williams reviewed gene: IFT122: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IDUA Eleanor Williams reviewed gene: IDUA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 IDS Eleanor Williams reviewed gene: IDS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 HUWE1 Eleanor Williams reviewed gene: HUWE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 GPC3 Eleanor Williams reviewed gene: GPC3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 GNPTAB Eleanor Williams reviewed gene: GNPTAB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 GNAS Eleanor Williams reviewed gene: GNAS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 GLI3 Eleanor Williams reviewed gene: GLI3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FREM1 Eleanor Williams reviewed gene: FREM1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FLNB Eleanor Williams reviewed gene: FLNB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FLNA Eleanor Williams reviewed gene: FLNA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FGFR3 Eleanor Williams reviewed gene: FGFR3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FGFR2 Eleanor Williams reviewed gene: FGFR2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FGFR1 Eleanor Williams reviewed gene: FGFR1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FGF9 Eleanor Williams reviewed gene: FGF9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FGF3 Eleanor Williams reviewed gene: FGF3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FBN1 Eleanor Williams reviewed gene: FBN1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 FAM20C Eleanor Williams reviewed gene: FAM20C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ESCO2 Eleanor Williams reviewed gene: ESCO2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ERF Eleanor Williams reviewed gene: ERF: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 EFNB1 Eleanor Williams reviewed gene: EFNB1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 EFNA4 Eleanor Williams reviewed gene: EFNA4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 EDNRB Eleanor Williams reviewed gene: EDNRB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 DHRS3 Eleanor Williams reviewed gene: DHRS3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CYP26B1 Eleanor Williams reviewed gene: CYP26B1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CTSK Eleanor Williams reviewed gene: CTSK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CRTAP Eleanor Williams reviewed gene: CRTAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 COLEC11 Eleanor Williams reviewed gene: COLEC11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 COLEC10 Eleanor Williams reviewed gene: COLEC10: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CHST3 Eleanor Williams reviewed gene: CHST3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CEP120 Eleanor Williams reviewed gene: CEP120: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CDC45 Eleanor Williams reviewed gene: CDC45: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CD96 Eleanor Williams reviewed gene: CD96: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 CCBE1 Eleanor Williams reviewed gene: CCBE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 BRAF Eleanor Williams reviewed gene: BRAF: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 BMP4 Eleanor Williams reviewed gene: BMP4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 BBS9 Eleanor Williams reviewed gene: BBS9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 B3GAT3 Eleanor Williams reviewed gene: B3GAT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 AXIN2 Eleanor Williams reviewed gene: AXIN2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ATR Eleanor Williams reviewed gene: ATR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ASXL1 Eleanor Williams reviewed gene: ASXL1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ARSB Eleanor Williams reviewed gene: ARSB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ALX4 Eleanor Williams reviewed gene: ALX4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ALX3 Eleanor Williams reviewed gene: ALX3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ALX1 Eleanor Williams reviewed gene: ALX1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ALPL Eleanor Williams reviewed gene: ALPL: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 AHDC1 Eleanor Williams reviewed gene: AHDC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ADAMTSL4 Eleanor Williams reviewed gene: ADAMTSL4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 ABCC9 Eleanor Williams reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ZIC1 Eleanor Williams Source NHS GMS was added to ZIC1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ZEB2 Eleanor Williams Source NHS GMS was added to ZEB2.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 WDR35 Eleanor Williams Source NHS GMS was added to WDR35.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 WDR19 Eleanor Williams gene: WDR19 was added
gene: WDR19 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: WDR19 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TWIST2 Eleanor Williams gene: TWIST2 was added
gene: TWIST2 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: TWIST2 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TWIST1 Eleanor Williams Source NHS GMS was added to TWIST1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TMCO1 Eleanor Williams Source NHS GMS was added to TMCO1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TLK2 Eleanor Williams Source NHS GMS was added to TLK2.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TICRR Eleanor Williams Source NHS GMS was added to TICRR.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TGFBR2 Eleanor Williams Source NHS GMS was added to TGFBR2.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TGFBR1 Eleanor Williams Source NHS GMS was added to TGFBR1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TCOF1 Eleanor Williams gene: TCOF1 was added
gene: TCOF1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: TCOF1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 TCF12 Eleanor Williams Source NHS GMS was added to TCF12.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 STAT3 Eleanor Williams Source NHS GMS was added to STAT3.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SPECC1L Eleanor Williams Source NHS GMS was added to SPECC1L.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SOX6 Eleanor Williams gene: SOX6 was added
gene: SOX6 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SOX6 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SOX10 Eleanor Williams gene: SOX10 was added
gene: SOX10 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SOX10 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SMO Eleanor Williams Source NHS GMS was added to SMO.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SMAD6 Eleanor Williams Source NHS GMS was added to SMAD6.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SLC3A2 Eleanor Williams gene: SLC3A2 was added
gene: SLC3A2 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SLC3A2 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SLC25A24 Eleanor Williams gene: SLC25A24 was added
gene: SLC25A24 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SLC25A24 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SKI Eleanor Williams Source NHS GMS was added to SKI.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SIX1 Eleanor Williams Source NHS GMS was added to SIX1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SHOC2 Eleanor Williams gene: SHOC2 was added
gene: SHOC2 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SHOC2 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SH3PXD2B Eleanor Williams Source NHS GMS was added to SH3PXD2B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SEC24D Eleanor Williams gene: SEC24D was added
gene: SEC24D was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SEC24D was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SCN4A Eleanor Williams gene: SCN4A was added
gene: SCN4A was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: SCN4A was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 SCARF2 Eleanor Williams Source NHS GMS was added to SCARF2.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 RUNX2 Eleanor Williams Source NHS GMS was added to RUNX2.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 RSPRY1 Eleanor Williams gene: RSPRY1 was added
gene: RSPRY1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: RSPRY1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 RECQL4 Eleanor Williams Source NHS GMS was added to RECQL4.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 RAB23 Eleanor Williams Source NHS GMS was added to RAB23.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 PTPRD Eleanor Williams gene: PTPRD was added
gene: PTPRD was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: PTPRD was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 PTPN11 Eleanor Williams gene: PTPN11 was added
gene: PTPN11 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: PTPN11 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 PRRX1 Eleanor Williams Source NHS GMS was added to PRRX1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 POR Eleanor Williams Source NHS GMS was added to POR.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 PHEX Eleanor Williams Source NHS GMS was added to PHEX.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 PAX3 Eleanor Williams gene: PAX3 was added
gene: PAX3 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: PAX3 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 P4HB Eleanor Williams gene: P4HB was added
gene: P4HB was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: P4HB was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 OSTM1 Eleanor Williams gene: OSTM1 was added
gene: OSTM1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: OSTM1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 NOG Eleanor Williams gene: NOG was added
gene: NOG was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: NOG was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 NFIX Eleanor Williams gene: NFIX was added
gene: NFIX was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: NFIX was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 MSX2 Eleanor Williams Source NHS GMS was added to MSX2.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 MEGF8 Eleanor Williams Source NHS GMS was added to MEGF8.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 MASP1 Eleanor Williams gene: MASP1 was added
gene: MASP1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: MASP1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 LRP5 Eleanor Williams Source NHS GMS was added to LRP5.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 LMX1B Eleanor Williams Source NHS GMS was added to LMX1B.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 KRAS Eleanor Williams Source NHS GMS was added to KRAS.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 KMT2D Eleanor Williams Source NHS GMS was added to KMT2D.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 KDM6A Eleanor Williams gene: KDM6A was added
gene: KDM6A was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: KDM6A was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 KAT6B Eleanor Williams gene: KAT6B was added
gene: KAT6B was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: KAT6B was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 KAT6A Eleanor Williams Source NHS GMS was added to KAT6A.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 KANSL1-AS1 Eleanor Williams gene: KANSL1-AS1 was added
gene: KANSL1-AS1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: KANSL1-AS1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 JAG1 Eleanor Williams Source NHS GMS was added to JAG1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IRX5 Eleanor Williams Source NHS GMS was added to IRX5.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IMPAD1 Eleanor Williams gene: IMPAD1 was added
gene: IMPAD1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: IMPAD1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IL11RA Eleanor Williams Source NHS GMS was added to IL11RA.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IHH Eleanor Williams Source NHS GMS was added to IHH.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IGF1R Eleanor Williams gene: IGF1R was added
gene: IGF1R was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: IGF1R was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IFT43 Eleanor Williams gene: IFT43 was added
gene: IFT43 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: IFT43 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IFT140 Eleanor Williams gene: IFT140 was added
gene: IFT140 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: IFT140 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IFT122 Eleanor Williams Source NHS GMS was added to IFT122.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IDUA Eleanor Williams Source NHS GMS was added to IDUA.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 IDS Eleanor Williams Source NHS GMS was added to IDS.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 HUWE1 Eleanor Williams Source NHS GMS was added to HUWE1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 GPC3 Eleanor Williams Source NHS GMS was added to GPC3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 GNPTAB Eleanor Williams Source NHS GMS was added to GNPTAB.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 GNAS Eleanor Williams Source NHS GMS was added to GNAS.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 GLI3 Eleanor Williams Source NHS GMS was added to GLI3.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FREM1 Eleanor Williams Source NHS GMS was added to FREM1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FLNB Eleanor Williams gene: FLNB was added
gene: FLNB was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: FLNB was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FLNA Eleanor Williams Source NHS GMS was added to FLNA.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FGFR3 Eleanor Williams Source NHS GMS was added to FGFR3.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FGFR2 Eleanor Williams Source NHS GMS was added to FGFR2.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FGFR1 Eleanor Williams Source NHS GMS was added to FGFR1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FGF9 Eleanor Williams gene: FGF9 was added
gene: FGF9 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: FGF9 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FGF3 Eleanor Williams gene: FGF3 was added
gene: FGF3 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: FGF3 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FBN1 Eleanor Williams Source NHS GMS was added to FBN1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 FAM20C Eleanor Williams Source NHS GMS was added to FAM20C.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ESCO2 Eleanor Williams Source NHS GMS was added to ESCO2.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ERF Eleanor Williams Source NHS GMS was added to ERF.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 EFNB1 Eleanor Williams Source NHS GMS was added to EFNB1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 EFNA4 Eleanor Williams Source NHS GMS was added to EFNA4.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 EDNRB Eleanor Williams gene: EDNRB was added
gene: EDNRB was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: EDNRB was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 DHRS3 Eleanor Williams Source NHS GMS was added to DHRS3.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CYP26B1 Eleanor Williams Source NHS GMS was added to CYP26B1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CTSK Eleanor Williams Source NHS GMS was added to CTSK.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CRTAP Eleanor Williams gene: CRTAP was added
gene: CRTAP was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: CRTAP was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 COLEC11 Eleanor Williams Source NHS GMS was added to COLEC11.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 COLEC10 Eleanor Williams gene: COLEC10 was added
gene: COLEC10 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: COLEC10 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CHST3 Eleanor Williams gene: CHST3 was added
gene: CHST3 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: CHST3 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CEP120 Eleanor Williams gene: CEP120 was added
gene: CEP120 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: CEP120 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CDC45 Eleanor Williams Source NHS GMS was added to CDC45.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CD96 Eleanor Williams gene: CD96 was added
gene: CD96 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: CD96 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 CCBE1 Eleanor Williams gene: CCBE1 was added
gene: CCBE1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: CCBE1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 BRAF Eleanor Williams gene: BRAF was added
gene: BRAF was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: BRAF was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 BMP4 Eleanor Williams gene: BMP4 was added
gene: BMP4 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: BMP4 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 BBS9 Eleanor Williams gene: BBS9 was added
gene: BBS9 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: BBS9 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 B3GAT3 Eleanor Williams gene: B3GAT3 was added
gene: B3GAT3 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: B3GAT3 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 AXIN2 Eleanor Williams gene: AXIN2 was added
gene: AXIN2 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: AXIN2 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ATR Eleanor Williams Source NHS GMS was added to ATR.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ASXL1 Eleanor Williams Source NHS GMS was added to ASXL1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ARSB Eleanor Williams gene: ARSB was added
gene: ARSB was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: ARSB was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ALX4 Eleanor Williams Source NHS GMS was added to ALX4.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ALX3 Eleanor Williams gene: ALX3 was added
gene: ALX3 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: ALX3 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ALX1 Eleanor Williams gene: ALX1 was added
gene: ALX1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: ALX1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ALPL Eleanor Williams Source NHS GMS was added to ALPL.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 AHDC1 Eleanor Williams gene: AHDC1 was added
gene: AHDC1 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: AHDC1 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ADAMTSL4 Eleanor Williams Source NHS GMS was added to ADAMTSL4.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 ABCC9 Eleanor Williams gene: ABCC9 was added
gene: ABCC9 was added to Craniosynostosis. Sources: NHS GMS
Mode of inheritance for gene: ABCC9 was set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.44 Louise Daugherty List of related panels changed from Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; GMS R100 to Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.42 Ellen McDonagh List of related panels changed from Craniosynostosis syndromes;Craniosynostosis syndromes phenotypes to Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; GMS R100
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.41 Ellen McDonagh Panel name changed from Craniosynostosis syndromes phenotypes to Craniosynostosis
List of related panels changed from Craniosynostosis syndromes to Craniosynostosis syndromes;Craniosynostosis syndromes phenotypes
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.40 SMO Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'Other' in order to capture variants within this gene in our current tiering pipeline.
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.40 SMO Rebecca Foulger Mode of inheritance for gene: SMO was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v1.39 ISCA-37441-Loss Louise Daugherty Region: ISCA-37441-Loss was added
Region: ISCA-37441-Loss was added to Craniosynostosis syndromes phenotypes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37441-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37441-Loss were set to 15852040; 16319823; 20140962
Phenotypes for Region: ISCA-37441-Loss were set to Potocki-Shaffer syndrome; multiple exostoses; biparietal foramina; intellectual disability; strabismus; minor craniofacial anomalies; myopia; ophthalmologic anomalies; 601224; mental retardation; enlarged anterior fontanel; genital abnormalities in males; parietal foramina; developmental delay
Rare syndromic craniosynostosis or isolated multisuture synostosis TLK2 Ellen McDonagh commented on gene: TLK2
Rare syndromic craniosynostosis or isolated multisuture synostosis TLK2 Ellen McDonagh classified TLK2 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis TLK2 Ellen McDonagh Added gene to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis ALX4 Louise Daugherty classified ALX4 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis ALX4 Louise Daugherty reviewed gene: ALX4
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Ellen McDonagh classified SMAD6 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis ALPL maurizia baldi commented on ALPL
Rare syndromic craniosynostosis or isolated multisuture synostosis DHRS3 Andrew Wilkie added DHRS3 to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis DHRS3 Andrew Wilkie reviewed DHRS3
Rare syndromic craniosynostosis or isolated multisuture synostosis TICRR Andrew Wilkie added TICRR to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis TICRR Andrew Wilkie reviewed TICRR
Rare syndromic craniosynostosis or isolated multisuture synostosis PRRX1 Andrew Wilkie added PRRX1 to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis PRRX1 Andrew Wilkie reviewed PRRX1
Rare syndromic craniosynostosis or isolated multisuture synostosis SIX1 Andrew Wilkie added SIX1 to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis SIX1 Andrew Wilkie reviewed SIX1
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Andrew Wilkie edited their review of SMAD6
Rare syndromic craniosynostosis or isolated multisuture synostosis KAT6A Louise Daugherty commented on KAT6A
Rare syndromic craniosynostosis or isolated multisuture synostosis CDC45 Louise Daugherty commented on CDC45
Rare syndromic craniosynostosis or isolated multisuture synostosis ASXL1 Louise Daugherty commented on ASXL1
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Louise Daugherty commented on SMO
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Louise Daugherty classified SMO as green
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Louise Daugherty edited their review of SMO
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Louise Daugherty classified SMO as amber
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Louise Daugherty commented on SMO
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Ellen McDonagh classified SMAD6 as red
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Ellen McDonagh commented on SMAD6
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Ellen McDonagh classified SMAD6 as red
Rare syndromic craniosynostosis or isolated multisuture synostosis TCF12 Andrew Wilkie edited their review of TCF12
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Andrew Wilkie added SMO to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis SMO Andrew Wilkie reviewed SMO
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Andrew Wilkie added SMAD6 to panel
Rare syndromic craniosynostosis or isolated multisuture synostosis SMAD6 Andrew Wilkie reviewed SMAD6
Rare syndromic craniosynostosis or isolated multisuture synostosis HUWE1 Andrew Wilkie edited their review of HUWE1
Rare syndromic craniosynostosis or isolated multisuture synostosis EFNB1 Ellen McDonagh commented on EFNB1